CA3097519A1 - Benzimidazole derivatives as modulators of retinoid-related orphan receptor gamma (ror.gamma.) and pharmaceutical uses thereof - Google Patents

Abstract

The present invention relates to benzimidazole derivatives of formula (I) as inhibitors of retinoid-related orphan receptor gamma (ROR?) protein, pharmaceutical compositions containing the compounds, preparation methods thereof, and the use of the compounds as therapeutic agents for the treatment of ROR?-mediated diseases or disorders.

Description

BENZIMIDAZOLE DERIVATIVES AS MODULATORS OF RETINOID-RELATED
ORPHAN RECEPTOR GAMMA (RORy) AND PHARMACEUTICAL USES THEREOF
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority under 35 U.S.C. 119(e) to U.S. Provisional Patent Application No. 62/666,312, filed on May 3, 2018, the disclosure of which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
The present invention relates to modulators of retinoid-related orphan receptor gamma (RORy) and their uses as therapeutic agents for treatment of RORy-mediated diseases or conditions, including various inflammation and autoimmune diseases and cancers.
BACKGROUND OF THE INVENTION
Nuclear receptors are ligand-regulated transcription factors that regulate development, immunity, and cellular metabolism, one of the major classes of drug targets for human diseases. The retinoid-related orphan receptor gamma (RORy) protein is a member of the NR1 subfamily of nuclear receptors and exhibits a typical nuclear receptor domain structure, consisting of the DNA binding domain; ligand binding domain; a hinge domain and activation function 2 domain (Benoit G, et al, Pharmacological Reviews, 58 (4):798-836, 2006; Zhang, Y., et al., Acta Pharmacogica Sinica, 36:71-87, 2015). RORy recognizes and binds as monomers, as opposed to most other nuclear receptors, which bind as dimers. It binds to specific DNA sequences, typically consisting of TAAA/ TNTAGGTCA, termed ROR response elements (ROREs).
There are two isoforms of RORy, RORyl and RORy2, which are produced from the same RORC gene, probably by selection of alternative promoters (Villey I, et al, Eur. J.
Immunol., 29(12):4072-80, 1999). RORy2 (also known as RORyt) produced from an mRNA
identical to that of RORyl except for a replacement of an alternative exon with two 5' -most exons, leading to a truncated form of RORyl. The two isoforms exhibit distinct patterns of tissue-specific expression. RORyt is preferentially expressed in the thymus and several distinct cell types of the immune system, whereas RORyl is expressed in many tissues, .. thymus, lung, kidney, muscle, and liver.
RORyt is a master regulator of the development of T helper 17 cells (Th17 cells) (Ruan, Q., et al., J. Exp. Med., 208(11):2321-2333, 2011; Ivanov, I. I. et al., Cell, 126:1121-1133, 2006). Th17 cells produce numerous cytokines, including interleukin-17 (IL-17), that are known to enhance inflammatory processes. In addition, a critical role of RORyt was shown in non-Th17 lymphoid cells expressing Thyl, SCA-1 and IL-23R proteins (Buonocore, S., et al., Nature, 464:1371-1375, 2010). RORyt plays an important role in the development of secondary lymphoid tissues, thymopoiesis, lymphocyte development ((Jetten, A. M., Nucl. Recep. Signal, 7:e300, D01:10.1621/nrs.07003, 2009). RORyl appears to be involved in the regulation of circadian rhythms (Guillaumond, F. et al, J.
Biol. Rhythms, 20 (5):391-403, 2005; Akashi M and Takumi T., Nat. Struct. Mol. Biol., 12 (5):441-448, 2005).
RORy has been identified as a key mediator in the pathogenesis of several diseases such as rheumatoid arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, Sjogren's syndrome and asthma, etc. (Louten et al, J. Allergy Clin.
Immunol., 123 : 1004-1011, (2009); Annuziato, F., et al, Nat. Rev. Rheumatol., 5(6): 325-331,2009; Lizuka, M., et al., J. Immunol., 194:56-67, 2014). Some other diseases, such as chronic dry eye disease, Kawasaki Disease, mucosal leishmaniasis, and Hashimoto's thyroiditis, are characterized by increased Th17 proportions and/or elevated levels of Th17 hallmark cytokines such as IL-17, IL-22 and IL-23 (Chen, Y., et al., Mucosal.
Immunol., 7(1):38-45, 2014; Jia, S., et al., Clin. Exp. Immunol., 162:131-137, 2010;
Boaventura, V. S., et al, Eur. J. Immunol., 40: 2830-2836, 2010; Figueroa-Vega, N., et al, J.
Clin. EndocrinoL
Metab., 95: 953-62, 2010). In each of the above examples the inhibition may be enhanced by simultaneous inhibition of RORoc. RORyt inhibitors are currently under development for the treatment of autoimmune diseases such as psoriasis and rheumatoid arthritis.
See Jun R. Huh and Dan R. Littman, Eur. J. Immunol., 42(9): 2232-2237 (2012), WO 2012/027965, WO
2013/029338, and US 2015/291607.
The present invention describes a series of new compounds that display potent inhibition against RORy, therefore, can provide a potential therapeutic approach to RORy-mediated diseases or conditions.
SUMMARY OF THE INVENTION
In one aspect, the present invention is directed to a compound of formula ( I
):
Ra R5a R5b (R7) (R4)s R3 N) A

R2 R1 Rb (I)

2 or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
¨ is selected from single bond and double bond, when¨a is double bond, then .. ¨ is single bond, Ra is absent and R6 is hydrogen; when ¨ is double bond, then ¨a is single bond, Ra is hydrogen and R6 is absent;
ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;
R1, R2 and R3 are identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cyano, amino, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
each R4 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -0R8, -C(0)0R8, -COR9, -NRioCOR9, -S(0)2R9, -NR10S(0)2R9, -CONRiiRi2, -NRiiRi2 and -S(0)2NRi iR12, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R5a and R56 are identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, cyano, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, -0R8, -NR10C0R9, -NR10C0CH20R8, _(CH2)8C(0)0R8, -(CH2)8CONRiiRi2 and -(CH2)8NRiiR12, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by .. one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, -CONRiiR12, -NRioCOR9, cycloalkyl, heterocyclyl, aryl and heteroaryl;
.5,0R8 or R5a and R56 are together form II
R6 is selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and NRiiR12, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more groups

3 selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
each R7 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -0R8, -C(0)0R8, -COR9, -NR1oCOR9, -S(0)2R9, -NRioS(0)2R9, -00NR11R12, -NR11R12 and -S(0)2NR11R12, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more group(s) selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R8 is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl and heterocyclyl, wherein said alkyl, aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen and alkoxy;
R9 is is selected from the group consisting of hydrogen, alkyl, hydroxyl, alkoxy, cycloalkyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
Rio is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl and heterocyclyl;
Ri 1 and R12 are identical or different and each is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, -COR13, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
or Rii and Ri2 together with the nitrogen atom to which they are attached form heterocyclyl, wherein heterocyclyl has one or more heteroatoms selected from the group consisting of 0, N and S, and is optionally substituted by one or more groups selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

4 Ri3 is selected from the group consisting of hydrogen, alkyl, hydroxyl, alkoxy, cycloalkyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
n is 0, 1, 2, 3, or 4;
s is 0, 1, 2, 3 or 4; and x is 0, 1, 2, 3 or 4.
In another aspect, the present invention is directed to a compound of formula ( IA ), Ra \ R5a /R5b R3 (R7)n ...---Br = biN Jo R2 R1 Rb 6R6 ( IA ) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is an intermediate for the synthesis of the compound of formula ( I ), wherein:
a b Ra, Rb, R1"-R3, R5a, R5b, R6, R7 and n are as defined in formula ( I ) .
In another aspect, the present invention is directed to a compound of formula ( IC ) or formula ( ID ) as an intermediate for the synthesis of compounds of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, Ra (1R4)s 0 R3 =(R7) Ra R5a R5b n NH OR5a R5b ,/(R7)n R
0 I (R4)s R
R

Rb 2 ( IC ) ( ID ) wherein:
Ra and Rb is hydrogen;
ring A, Ri-R4, R5a, R5b, R6, R7, n and s are as defined in formula ( I ).

5 In another aspect, the present invention is directed to various processes for preparing the compound of formula ( I ).
In another aspect, the present invention is directed to a pharmaceutical composition comprising a compound of formula ( I ), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
In another aspect, the present invention is directed to a method for inhibiting a retinoid-related orphan receptor gamma (RORy) or treating a retinoid-related orphan receptor gamma (RORy) protein mediated disease or disorder in a subject using a therapeutically effective amount of the compound of formula (I), or the tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
Other aspects and advantages of the present invention will be better appreciated in view of the following detailed description and claims.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the present invention is directed to a compound of formula ( I
):
R5a R5b R Ra (R4) 3s = bi A

R2 R1 Rb (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
¨ is selected from single bond and double bond, when¨a is double bond, then ¨ is single bond, Ra is absent and Rb is hydrogen; when ¨ is double bond, then is single bond, Ra is hydrogen and Rb is absent;
ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;
Ri, R2 and R3 are identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cyano, amino, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;

6 each R4 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -0R8, -C(0)0R8, -COR9, -NR10C0R9, -S(0)2R9, -NRioS(0)2R9, -00NR11R12, -NR11R12 and -S(0)2NRi iR12, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R5a and R5b are identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, cyano, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, -0R8, -NR10C0R9, -NR10C0CH20R8, _(CH2)8C(0)0R8, -(CH2)8CONRi1R12 and -(CH2)8NRi1R12, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, -CONR11R12, _NR10C0R9, cycloalkyl, heterocyclyl, aryl and heteroaryl;
5,0R8 or R5a and R5b are together form II
R6 is selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and NR11R12, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
each R7 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -0R8, -C(0)0R8, -COR9, -NR10C0R9, -S(0)2R9, -NR10S(0)2R9, -CONR11R12, -NR11R12 and -S(0)2NR1 iR12, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more group(s) selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R8 is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl and heterocyclyl, wherein said alkyl, aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen and alkoxy;

7 R9 is is selected from the group consisting of hydrogen, alkyl, hydroxyl, alkoxy, cycloalkyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
Rio is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl and heterocyclyl;
Ri 1 and R12 are identical or different and each is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, -COR13, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
or Rii and R12 together with the nitrogen atom to which they are attached form heterocyclyl, wherein heterocyclyl has one or more heteroatoms selected from the group consisting of 0, N and S, and is optionally substituted by one or more groups selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R13 is selected from the group consisting of hydrogen, alkyl, hydroxyl, alkoxy, cycloalkyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
n is 0, 1, 2, 3, or 4;
s is 0, 1, 2, 3 or 4; and x is 0, 1, 2, 3 or 4.
In some embodiments of the present invention, the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is a compound of formula ( Ia ) or formula (lb):

8 R5a R5b R5a R5b (R7)n (ROI, (R4)s R3 N (R4)s R3 N
NH rc0 0 41 0 R

( la ) ( lb ) wherein:
R5a, R5b, R6, R7, n and s are as defined in formula (I).
In some embodiments of the present invention, in a compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, ring A is selected from the group consisting of phenyl, C3_6 cycloalkyl and 5 or 6 member heteroaryl, preferably piperidinyl, phenyl, thienyl, furyl and pyridinyl.
In some embodiments of the present invention, the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is a compound of formula ( II ):
Ra \ R5a R5b (R7) R3 N n R4)s ID!
N

Rb R

R2 Ri ( II ) wherein:
a b Ra, Rb, R1-R4, R5a, R56, R6, R7, n and s are as defined in formula ( I ) .
In some embodiments of the present invention, the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is a compound of formula ( IIa ):
Ra \ R5a R5b R3 N (R7)n N I
1 -C) Rb 0 R6 R4 R2 Ri ( ha) wherein:

9 ¨a, Ra, Rb, Ri-R4, R5a, R5b, R6, R7 and n are as defined in formula ( I ).
In some embodiments of the present invention, the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is a compound of formula ( III ):
Ra R5a R5b R3 (R7)n a IDI
R

R2 R1 Rb ( III ) wherein:
a b ¨ --------------- ¨ Ra, Rb, Ri-R4, R5a, R5b, R6, R7, n and s are as defined in formula ( I ) .
In some embodiments of the present invention, the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is a compound of formula ( ):
R5a R5b Ras, (R7)n R4b R4a>CN

R2 R1 Rb ( Illa ) wherein:
R4a and R4b are identical or different and each is independently selected from the group consisting of halogen, hydrogen, alkyl and haloalkyl;
a b ¨ --------------- ¨ Ra, Rb, Ri-R3, R5a, R5b, R6, R7 and n are as defined in formula ( I ).
In some embodiments of the present invention, in the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, each R4 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, -0R8 and -NR11R12;
Rg, Rii and Ri2 are as defined in formula ( I ).
In some embodiments of the present invention, in the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, Ri, R2, and R3 are identical or different and each is independently selected from the group consisting of hydrogen, halogen and alkyl.
In some embodiments of the present invention, in the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, R5a and R56 are identical or different and each is independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, -0R8, -NR10C0R9, -NR10C0CH20R8, _(CH2)xC(0)0R8, -(CH2)xCONRi1R12 and -(CH2)xNRi iRi2;
sj-OR8 or R5a and R56 are together form H ; R8 to R12 and x are as defined in formula ( I ).
In some embodiments of the present invention, in the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, R6 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocyclyl and -NR11R12, wherein said alkyl is optionally substituted by one or more groups selected from the group consisting of alkoxy and cycloalkyl.
In some embodiments of the present invention, in the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, R7 is selected from the group consisting of hydrogen, halogen and alkyl.
Typical compounds of the present invention include, but are not limited to, Example Compound Name No.
-o o' CI

CI
H
4,6 -dichloro-2- (4- (ethylsulfo nyl)benzy1)-5 -phenyl- 1H-benzo [di imidazole ¨\ 0 CI

CI

(4,6-dichloro-5-pheny1-1H-benzo[dlimidazo1-2-y1)(4-(ethylsulfonyl)phenyl)methanol ¨\ 0 O.
CI

4,6-dichloro-2-(4-(ethylsulfonyl)benzy1)-5-(2-(trifluoromethyl)pheny1)-1H-benzo[d]imidazo1e - ,0 -s-CI
ci OCF3 2-(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo[dlimidazo1-2-y1)-2-(4-(ethylsulfonyl)phenyl)ethanol ¨\ .0 ,s-= CI

(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo[dlimidazo1-2-y1)(4-(ethylsulfonyl)phenyl)methanol ,0 s-0, a \mf N
OCH, 2-(4,6-dichloro-5-(2-methoxypheny1)-1H-benzo[dlimidazo1-2-y1)-2-(4-(ethylsulfonyl)phenyl)ethanol - ,0 s-CI
ci OCH3 (4,6-dichloro-5-(2-methoxypheny1)-1H-benzo[cflimidazo1-2-y1)(4-(ethylsulfonyl)phenyl)methanol - ,0 -0-s CI

4,6-dichloro-2-(4-(ethylsulfonyl)benzy1)-5-(2-isopropoxypheny1)-1H-benzo[d]imidazo1e 0*s*
CI

2-(4,6-dichloro-5-(2-isopropoxypheny1)-1H-benzo[dlimidazo1-2-y1)-2-(4-(ethylsulfonyl)phenyl)ethanol ¨\ .0 ,s-CI
HO N

10 (4,6-dichloro-5-(2-isopropoxypheny1)-1H-benzo[dlimidazo1-2-y1)(4-(ethylsulfonyl)phenyl)methanol ¨\ .0 s-o*
CI
HO N CI

11 11 2-(4,6-dichloro-5-(2-fluoropheny1)-1H-benzo[dlimidazo1-2-y1)-2-(4-(ethylsulfonyl)phenyl)ethanol ¨\ .0 CI

12 HO N
CI

(4,6-dichloro-5-(2-fluoropheny1)-1H-benzo[dlimidazo1-2-y1)(4-(ethylsulfonyl)phenyl)methanol ¨\ -0 0'S' a a µWf N

13 oo N a = 13 4,6-dichloro-2-(4-(ethylsulfonyl)benzy1)-5-(2-(methoxymethoxy)pheny1)-1H-benzo[d]imidazo1e õ0 a a N
HO N CI

14 14 2-(4,6-dichloro-5-(2-methoxymethoxypheny1)-1H-benzo[dlimidazo1-2-y1)-2-(4-(ethylsulfonyl)phenyl)ethanol ¨\ 0 CI
CI

15 HO N
CI
CI
(4,6-dichloro-5-(2,5-dichloropheny1)-1H-benzo[dlimidazo1-2-y1)(4-(ethylsulfonyl)phenyl)methanol ¨\ -0 CI
NQ

16 CI

4,6-dichloro-5-(2-ethoxypheny1)-2-(4-(ethylsulfonyl)benzy1)-1H-benzo[d]imidazo1e ,0 =
N CI
HO hi a ------

17 17 2-(4,6-dichloro-5-(2-ethoxypheny1)-1H-benzo[dlimidazo1-2-y1)-2-(4-(ethylsulfonyl)phenyl)ethanol ,0 ,s' 0' CI
\m' N
HO N a

18 (4,6-dichloro-5-(2-ethoxypheny1)-1H-benzo[dlimidazo1-2-y1)(4-(ethylsulfonyl)phenyl)methanol ,0 os a c, N

19 19 4,6-dichloro-2-(4-(ethylsulfonyl)benzy1)-5-(2-(2-methoxyethoxy)pheny1)-1 H-benzo1dlimidazole 0, a c, \wf N
HO N ci

20 2-(4,6-dichloro-5-(2-(2-methoxyethoxy)pheny1)-1H-benzokllimidazo1-2-y1)-2-(4-(ethylsulfonyl)phenyl)ethanol ,0 a c, N
HO /H CI (:)`-"--'0".-

21 21 (4,6-dichloro-5-(2-(2-methoxyethoxy)pheny1)-1H-benzo1dlimidazo1-2-y1)(4-(ethylsulfonyl)phenyl)methanol o 0-s CI
CI CN
N

22 HO

2-(4,6-dichloro-2-(1-(4-(ethylsulfonyl)pheny1)-2-hydroxyethyl)-1H-benzokllimidazo1-5-y1)benzonitrile s-CI
HO N CICN

23 23 2-(4,6-dichloro-2-((4-(ethylsulfonyl)phenyl)(hydroxy)methyl)-1H-benzokllimidazo1-5-y1)benzonitrile ,o -o-s

24 4,6-dichloro-2-(4-(ethylsulfonyflbenzy1)-5-(thiophen-3-y1)-1H-benzo[dlimidazo1e ¨\ .0 s-¨

25 HO N CI
2-(4,6-dichloro-5-(thiophen-3-y1)-1H-benzokflimidazo1-2-y1)-2-(4-(ethylsulfonyflphenyflethanol ¨\ .0 =01 HO N CI

26 26 (4,6-dichloro-5-(thiophen-3-y1)-1H-benzo[dlimidazo1-2-y1)(4-(ethylsulfonyl)phenyl)methanol ,0 a ci \Wf N
H CI /

27 2-(4,6-dichloro-2-(4-(ethylsulfonyebenzy1)-1H-benzokflimidazo1-5-y1)-N,N-dimethylaniline ¨\ -0 o'S
a a µMf N
N a OCHF2

28 4,6-dichloro-5-(2-(difluoromethoxy)pheny1)-2-(4-(ethylsulfonyflbenzy1)-1H-benzo[dlimidazo1e ,s' a o_= N

29 2-(4,6-dichloro-5-(2-(difluoromethoxy)pheny1)-1H-benzokflimidazo1-2-y1)-2-(4-(ethylsulfonyflphenyflethanol s-cp a µM' N
HO N CIOCHF, -

30 (4,6-dichloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo[dlimidazo1-2-y1)(4-(ethylsulfonyl)phenyl)methanol ,o 0,s-c, µwi N
N

31 31 4,6-dichloro-2-(4-(ethylsulfonyflbenzy1)-5-(2-(2,2,2-trifluoroethoxy)pheny1)-1H-benzo[dlimidazo1e , 0 CI
µMi N
HO N a 0,CF3

32 2-(4,6-dichloro-5-(2-(2,2,2-trifluoroethoxy)pheny1)-1H-benzo[dlimidazo1-2-y1)-2-(4-(ethylsulfonyflphenyl)ethanol ,0 ci N
HO N ci 0,CF3

33 33 (4,6-dichloro-5-(2-(2,2,2-trifluoroethoxy)pheny1)-1H-benzo[dlimidazo1-2-y1)(4-(ethylsulfonyl)phenyl)methanol ,o o's CI

34 4,6-dichloro-2-(4-(ethylsulfonyflbenzy1)-5-(2-(3,3,3-trifluoropropyflpheny1)-1H-benzo[dlimidazo1e ,0 o,s aa \M' N

35 (4,6-dichloro-5-(2-(3,3,3-trifluoropropyflpheny1)-1H-benzo[dlimidazo1-2-y1)(4-(ethylsulfonyl)phenyl)methanol - ,0 -0-s a a \MI N
N CI

36 4,6-dichloro-2-(4-(ethylsulfonyl)benzy1)-5-(2-isopropylpheny1)-1H-benzo[d]imidazo1e ¨\ -0 * N CI
HO hi a

37 37 2-(4,6-dichloro-5-(2-isopropylpheny1)-1H-benzo[dlimidazo1-2-y1)-2-(4-(ethylsulfonyl)phenyl)ethanol 0- ,0 ,s--= CI
/ OCHF, HO-N N CI -

38 (E,Z)-(4,6-dichloro-5-(2-(difluoromethoxy)pheny1)-1H-benzokflimidazo1-2-y1)(4-(ethylsulfonyl)phenyl)methanone wdme ¨\ .0 s-CI

39 (4,6-dichloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo[cflimidazo1-2-y1)(4-(ethylsulfonyl)phenyl)methanamine ¨\
,s-a a \M/ N

>\-NH a OCHF,

40 40 N-44,6-dichloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo[dlimidazo1-2-y1)(4-(ethylsulfonyl)phenyl)methyl)acetamide ¨\ .0 0-s-,11 N

41 0CH62 </0 N-44,6-dichloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo[dlimidazo1-2-y1)(4-(ethylsulfonyflphenyflmethyl)-2-methoxyacetamide ,o os-NQ
a ocHF2 * CI

) 4)=-,LNH

42 N-44,6-dichloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo[dlimidazo1-2-y1)(4-(ethylsulfonyephenyflmethyl)-3,5-dimethylisoxazole-4-carboxamide o (Ds CI

43 HN N CI OCF3 (4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo[cflimidazo1-2-y1)(4-(ethylsulfonyl)phenyl)methanamine NQ
(:)õs CI

44 44 N-44,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo[dlimidazo1-2-y1)(4-(ethylsulfonyl)phenyl)methyl)acetamide -o o's-* a N CI F,

45 4,6-dichloro-2-(4-(methylsulfonyflbenzy1)-5-(2-(trifluoromethyl)pheny1)-1H-benzo[dlimidazo1e -o s' cp * ci /1\I

46 46 2-(4,6-dichloro-5-(2-(trifluoromethyflpheny1)-1H-benzokflimidazo1-2-y1)-2-(4-(methylsulfonyflphenyflethanol NQ
N.
0-s ci ci OCHF2

47 4,6-dichloro-5-(2-(difluoromethoxy)pheny1)-2-(4-(methylsulfonyl)benzy1)-1H-benzo[dlimidazo1e ,0 s-ci 0cHF2 CI
HO N

48 2-(4,6-dichloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo Mimidazo1-2-y1)-2-(4-(methylsulfonyl)phenyl)ethanol ,o (Ds ci

49 (4,6-dichloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo[dlimidazo1-2-y1)(4-(methylsulfonyl)phenyl)methanol \¨\ 0 o,s a a \mi N
N a OCF3

50 4,6-dichloro-2-(4-(propylsulfonyl)benzy1)-5-(2-(trifluoromethoxy)pheny1)-1H-benzo[dlimidazo1e ,0 ,s-CI

51 HO N CIOC F3 2-(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo Mimidazo1-2-y1)-2-(4-(propylsulfonyl)phenyeethanol \--\
so )R4, ci Ho OCF,

52 52 (4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo[cflimidazo1-2-y1)(4-(propylsulfonyl)phenyl)methanol ¨0 O'S
CI
\W' N

53 N a OCF, 4,6-dichloro-2-(4-((2-methoxyethyl)sulfonyl)benzy1)-5-(2-(trifluoromethoxy)pheny1)-1H-benzokflimidazole ¨0 N CI

54 Ho h, 010CF, 2-(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo[dlimidazo1-2-y1)-2-(4-((2-methoxyethyl)sulfonyl)phenyl)ethanol ¨0 ,0 CI
N

55 HO N CIOCF, (4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo[cflimidazo1-2-y1)(4-((2-methoxyethyl)sulfonyl)phenyl)methanol ,0 0--s a \Mf N

56 4,6-dichloro-2-(4-(methylsulfonyl)benzy1)-5-(2-(trifluoromethoxy)pheny1)-1H-benzo[cflimidazo1e \ .0 s-

57 2-(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo[dlimidazo1-2-y1)-2-(4-(methylsulfonyl)phenyl)ethanol .o s-CI

58 Ho N 0100F3 (4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo[dlimidazo1-2-y1)(4-(methylsulfonyl)phenyl)methanol CI
N OCF,

59 4,6-dichloro-2-(4-((2,2,2-trifluoroethyl)sulfonyl)benzy1)-5-(2-(trifluoromethoxy)pheny1)-1H-benzo[dlimidazole F) 0' CI
\WfcI
/1\I
OC

60 HO N CI F3 2-(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo[dlimidazo1-2-y1)-2-(4-((2,2,2-trifluoroethyl)sulfonyl)phenyl)ethanol F\_\5,0 CI

61 C

4,6-dichloro-2-(4-((2-fluoroethyl)sulfonyebenzy1)-5-(2-(trifluoromethoxy)pheny1)-1H-benzo[dlimidazole Fx_vo \m' N
OCF, HO N CI

62 62 2-(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo[dlimidazo1-2-y1)-2-(4-42-fluoroethypsulfonyephenyl)ethanol F\_\
*() cys CI
/IA

63 N CI CF3 4,6-dichloro-2-(4-((2-fluoroethyl)sulfonyebenzy1)-5-(2-(trifluoromethyl)pheny1)-1H-benzokflimidazole F\_\ 0 a c, \Mf N

64 HO N CI CF3 2-(4,6-dichloro-5-(2-(trifluoromethyl)pheny1)-1H-benzokflimidazo1-2-y1)-2-(4-42-fluoroethypsulfonyephenyl)ethanol F F
F-(0 , O'S
CI
N a CF3

65 4,6-dichloro-5-(2-(trifluoromethyflpheny1)-2-(4-((trifluoromethyl)sulfonyl)benzy1)-1H-benzokflimidazole , cy-s CI
N

66 CI OCF3 4,6-dichloro-2-(4-((cyclopropylmethyl)sulfonyflbenzy1)-5-(2-(trifluoromethoxy)pheny1)-1H-benzokflimidazole ,0 a c,

67 2-(4-((cyclopropylmethypsulfonyflpheny1)-2-(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzokflimidazo1-2-yflethanol r>---c,

68 Os*
OCF, HO N CI

(4-((cyclopropylmethyl)sulfonyl)phenyl)(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo[dlimidazo1-2-y1)methanol 0, = a N
NN.CI CF3

69 4,6-dichloro-2-(4-((cyclopropylmethyl)sulfonyl)benzy1)-5-(2-(trifluoromethyl)pheny1)-1H-benzo[d]imidazole CI

70 2-(4-((cyclopropylmethypsulfonyl)pheny1)-2-(4,6-dichloro-5-(2-(trifluoromethyl)pheny1)-1H-benzo[dlimidazo1-2-y1)ethanol ,0 =
N

71 HO hi a CF3 (4-((cyclopropylmethyl)sulfonyl)phenyl)(4,6-dichloro-5-(2-(trifluoromethyl)pheny1)-1H-benzo[dlimidazo1-2-y1)methanol a a µMi N

72 4,6-dichloro-2-(4-((cyclopropylmethyl)sulfonyl)benzy1)-5-(2-(difluoromethoxy)pheny1)-1H-benzo[d]imidazole aa \m' N
HO N CIOCHF, -H

73 73 2-(4-((cyclopropylmethypsulfonyl)pheny1)-2-(4,6-dichloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo[dlimidazo1-2-y1)ethanol so 1>--\
* N
HO N CI F
'74

74 2-(4-((cyclopropylmethyl)sulfonyl)pheny1)-2-(4,6-dichloro-5-(2-fluoropheny1)-1H-benzo[dlimidazo1-2-y1)ethanol * CI

75 HO N CI
(4-((cyclopropylmethyl)sulfonyl)phenyl)(4,6-dichloro-5-(2-fluoropheny1)-1H-benzo[dlimidazo1-2-y1)methanol FvF
ci 0 F
HN
= CI

76 4,6-dichloro-2-(4-(ethylsulfony1)-2-fluorobenzy1)-5-(2-(trifluoromethoxy)phenyl)-1H-benzo[dlimidazole FvF
ci 0 F
HN
= CI

77 2-(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo[dlimidazo1-2-y1)-2-(4-(ethylsulfonyl)-2-fluorophenyl)ethanol FvF
ci 0 F
&1 HN
= CI
F OH

78 78 (4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo[dlimidazo1-2-y1)(4-(ethylsulfonyl)-2-fluorophenyl)methanol CI CF, N CI

79 F OH

(4,6-dichloro-5-(2-(trifluoromethyl)pheny1)-1H-benzo[dlimidazo1-2-y1)(4-(ethylsulfonyl)-2-fluorophenyl)methanol CI oYF

-==="" -'1\I .. CI

80 F ao 4,6-dichloro-2-(4-((cyclopropylmethyl)sulfony1)-2-fluorobenzy1)-5-(2-(trifluoromethoxy)phenyl)-1H-benzokflimidazole F)LF
CI o = HN

81 2-(4-((cyclopropylmethyl)sulfony1)-2-fluoropheny1)-2-(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzokflimidazol-2-yflethanol F)LF

AJO
= HN

82 F OH

(4-((cyclopropylmethyl)sulfony1)-2-fluorophenyl)(4,6-dichloro-5-(2-(trifluoromethoxy)phenyl)-1H-benzokflimidazo1-2-yflmethanol F)_F
Cl 0 = HN

83 4,6-dichloro-5-(2-(difluoromethoxy)pheny1)-2-(4-(ethylsulfony1)-2-fluorobenzyl)-1H-benzokllimidazole F)_F

HN

84 OH

2-(4,6-dichloro-5-(2-(difluoromethoxy)pheny1)-1H-benzokflimidazo1-2-y1)-2-(4-(ethylsulfony1)-2-fluorophenyflethanol =

= HN
CI

85 F OH
(4,6-dichloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo1dlimidazo1-2-y1)(4-(ethylsulfony1)-2-fluorophenyflmethanol YCI OF
HN
= CI

86 4,6-dichloro-2-(2-chloro-4-(ethylsulfonyl)benzy1)-5-(2-(trifluoromethoxy)pheny1)-1H-benzo[d]imidazole F)LF

HN

87 CI

2-(2-chloro-4-(ethylsulfonyl)pheny1)-2-(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo[dlimidazo1-2-y1)ethanol yF
CI o J(jai HN
= CI

88 CI OH 88 (2-chloro-4-(ethylsulfonyl)phenyl)(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo[dlimidazo1-2-y1)methanol OF¨F
Cl ,C 111110 HN
= CI

89 CI 89 4,6-dichloro-2-(2-chloro-4-(ethylsulfonyl)benzy1)-5-(2-(difluoromethoxy)pheny1)-1H-benzo[d]imidazole .6C'11111 HN

90 CI 90 4,6-dichloro-2-(2-chloro-4-((cyclopropylmethyl)sulfonyl)benzy1)-5-(2-(trifluoromethoxy)pheny1)-1H-benzo[d]imidazole F)LF
CI o HN

91 CI

2-(2-chloro-4-((cyclopropylmethyl)ethylsulfonyl)pheny1)-2-(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo[dlimidazol-2-y1)ethanol CI OF)LF
(:),0 H a

92 a OH

(2-chloro-4-((cyclopropylmethyl)sulfonyl)phenyl)(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo kflimidazo1-2-yflmethanol CI CI
(1,0 ---- HN,N a

93 4,6-dichloro-2-(2-chloro-4-((cyclopropylmethyl)sulfonyl)benzy1)-5-(2-chloropheny1)-1H-benzo [di imidazole Cl CI
Ch),0 H% a OH

94 94 (2-chloro-4-((cyclopropylmethyl)sulfonyl)phenyl)(4,6-dichloro-5-(2-chloropheny1)-1H-benzokflimidazo1-2-y1)methanol CI NC
(g,0 HNI,,N a

95 95 4,6-dichloro-2-(2-chloro-4-((cyclopropylmethyl)sulfonyl)benzy1)-5-(2-cyanopheny1)-1H-benzokflimidazole a HO

96 (:)0 MO HIV_ N oi OH

2-(2-chloro-4-((cyclopropylmethyl)ethylsulfonyflpheny1)-2-(4,6-dichloro-5-(2-cyanopheny1)-1H-benzo[dlimidazol-2-y1)ethanol CI NC
A JO
HN, N CI
OH

97 97 (4-((cyclopropylmethyl)sulfonyl)phenyl)(4,6-dichloro-5-(2-cyanopheny1)-1H-benzo [di imidazol-2-yl)methanol F)_F

98 HN

4,6-dichloro-2-(4-((cyclopropylmethyl)sulfony1)-2-fluorobenzy1)-5-(2-(difluoromethoxy)phenyl)-1H-benzo[dlimidazole F
CI 0)-F
A',-;P/irh HN

99 OH

2-(4-((cyclopropylmethyl)sulfony1)-2-fluoropheny1)-2-(4,6-dichloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo[dlimidazol-2-y1)ethanol AJ111111h HN
qtlir

100 F OH

(4-((cyclopropylmethyl)sulfony1)-2-fluorophenyl)(4,6-dichloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[dlimidazo1-2-Amethanol yF
CI o = HN
CI

101 CI 101 4,6-dichloro-2-(2-chloro-4-(methylsulfonyl)benzy1)-5-(2-(trifluoromethoxy)pheny1)-1H-benzo[d]imidazole F)LF

= HN
CI

102 a oFi 102 2-(2-chloro-4-(methylsulfonyl)pheny1)-2-(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo[dlimidazo1-2-y1)ethanol F)LF

12,0 HN
-IA a

103 CI OH

(2-chloro-4-(methylsulfonyl)phenyl)(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo[dlimidazo1-2-y1)methanol F)LF
Cl 0

104 ----r- HN

4,6-dichloro-2-(4-((iso-propyl)sulfonyflbenzy1)-5-(2-(trifluoromethoxy)pheny1)-1H-benzokflimidazole F)/iF

-.NI CI

105 OH

2-(4-((iso-propyl)sulfonyl)pheny1)-2-(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzokflimidazo1-2-yflethanol yo F
clo HN

106 N CI
OH

(4-((iso-propyl)sulfonyl)phenyl)(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo[dlimidazo1-2-Amethanol sO
-a a N

107 HO N CICF, 2-(4,6-dichloro-5-(2-(trifluoromethyl)pheny1)-1H-benzokflimidazo1-2-y1)-2-(4-((iso-propyl)sulfonyflphenyl)ethanol F, y¨F

0,0 = HN

108 =F

2-(4-(ethylsulfonyflbenzy1)-4,6-difluoro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo[dlimidazo1e F= FXF
HN,N F

109 OH 109 2-(4,6-difluoro-5-(2-(trifluoromethoxy)pheny1)-1H-benzokflimidazo1-2-y1)-2-(4-(ethylsulfonyl)phenyflethanol F
= H F

110 OH 110 (4,6-difluoro-5-(2-(trifluoromethoxy)pheny1)-1H-benzoldlimidazo1-2-y1)(4-(ethylsulfonyl)phenyl)methanol F F
j' e HN
"Pr = F

111 111 2-(4-(ethylsulfonyl)benzy1)-4,6-difluoro-5-(2-(trifluoromethyl)pheny1)-1H-benzoldlimidazo1e F F
ch,0 40 HN.., N F

112 OH 112 2-(4,6-difluoro-5-(2-fluoropheny1)-1H-benzoldlimidazo1-2-y1)-2-(4-(ethylsulfonyl)phenyl)ethanol 4111 HN, OH

113 113 (4,6-difluoro-5-(2-methoxypheny1)-1H-benzoldlimidazo1-2-y1)(4-(ethylsulfonyl)phenyl)methanol 40 HN,,N F

114 OH 114 2-(4,6-difluoro-5-pheny1-1H-benzoldlimidazo1-2-y1)-2-(4-(ethylsulfonyl)phenyl)ethanol ,o , -o-s

115 2-(4-(ethylsulfonyl)benzy1)-4,6-dimethy1-5-(2-(trifluoromethyl)phenyl)-1H-benzoldlimidazo1e

116 40 HN,,N

2-(4,6-dimethy1-5-(2-(trifluoromethyl)pheny1)-1H-benzo[dlimidazo1-2-y1)-2-(4-(ethylsulfonyl)phenyflethanol j-- 0 HN

117 OH 117 2-(4-(ethylsulfonyflpheny1)-2-(5-(2-methoxypheny1)-4,6-dimethyl-1H-benzo[dlimidazo1-2-y1)ethanol J(jai HN
--1\1

118 OH

(4-(ethylsulfonyl)phenyl)(5-(2-methoxypheny1)-4,6-dimethyl-1H-benzokflimidazo1-2-yflmethanol F)LCI O F

119 HO 119 2-(6-chloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzokflimidazo1-2-y1)-2-(4-(ethylsulfonyflphenyl)ethanol F
HNJJ

120 HO 120 2-(4-(ethylsulfonyflpheny1)-2-(6-fluoro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo[dlimidazo1-2-y1)ethanol F OF)LF
HN

121 OH 121 (4-(ethylsulfonyl)phenyl)(6-fluoro-5-(2-(trifluoromethoxy)pheny1)-1H-benzokflimidazo1-2-yflmethanol FF

122 &N4 HN
H

N-c ycloprop y1-4-44 ,6-dichloro-5 -(2-(trifluoromethoxy)pheny1)-1H-b enzo [di imidazol-2-yflmethyl)benzenesulfonamide Fx_F
a 0 F
&NIP H HN,, N CI

123 HO 123 N-cyclopropy1-4-(1-(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo kflimidazo1-2-y1)-2-hydroxyethyl)benzenesulfonamide CI
AJO HN,N

124 HO 124 2-(6-chloro-5-(2-isopropoxypheny1)-1H-benzo [di imidazol-2-y1)-2-(4-((c ycloprop ylmethyl)sulfonyflphenyl)ethanol HN
(s)-'1\1 (S)-2-(6-chloro-5-(2-isopropoxypheny1)-1H-benzo [dlimidazol-2-y1)-2-(4-((cyclopropylmethyl)sulfonyflphenyl)ethanol Ajoish HN
lir _0,1-NI
124-2 He 124-2 (R)-2-(6-chloro-5-(2-isopropoxypheny1)-1H-benzokflimidazo1-2-y1)-2-(4-((cyclopropylmethyl)sulfonyflphenyl)ethanol HN NI-/

125 125 4,6-dichloro-5-(4,4-difluoropiperidin-1-y1)-2-(4-(ethylsulfonyl)benzy1)-1H-benzo[d]imidazo1e FF.CN y ci H

126 126 OH
2-(5,7-dichloro-6-(4,4-difluoropiperidin-l-y1)-1H-benzo kflimidazo1-2- y1)-2-(4-(ethylsulfonyl)phenyflethanol ci a FN1 OH

(R)-2-(5 ,7-dichloro-6-(4,4-difluorop iperidin-1- y1)- 1H-benzo [di imid azol-2-34)-2-(4-(ethylsulfonyflphenyflethanol 04,v FF.cN y CI
126-2 126-2 *-'0H
(S)-2-(5,7-dichloro-6-(4,4-difluoropiperidin-l-y1)-1H-benzo imidazo1-2- y1)-2-(4-(ethylsulfonyflphenyflethanol a FcN y CI

127 127 5,7 -dichloro-2-(4-((cyc loprop ylmethyl)sulfonyflb enz y1)-6-(4,4-difluorop iperidin-1 - y1)-1H-benzo [di imid azole 0, p \S
=
F
N N

128 H2 CI

2-(7-chloro-6-(2-(difluoromethoxy)pheny1)-1H-benzo [di imid azol-2- y1)-2-(4-((c yc loprop ylmethyl)sulfonyflphenyflethanamine oy-NH

CI NH

129 N-(2-(7-chloro-6-(2-(difluoromethoxy)pheny1)-1H-benzo imidazol-2- y1)-2-(4-((cyc loprop ylmethyl)sulfonyflphenyflethyflacetamide oCI

130 FF>cN Nr.,,,H 0 OH
CI

3 -(4,6-dichloro-5-(4,4 -difluoropiperidin- 1 - y1)- 1H-benzo kflimidazo1-2-y1)-3 -(4-(ethylsulfonyflphenyflpropanoic acid 04,v * N
F7\_/
NH,

131 131 0 3 -(4,6-dichloro-5-(4,4 -difluoropiperidin- 1 - y1)- 1H-benzo1dlimidazol-2-y1)-3 -(4-(ethylsulfonyflphenyflpropanamide CI NI_ NH MIIP
-Tc) CI 132

132 4,6-dichloro-2-(4-((cyclopropylmethyl)sulfonyflbenzy1)-5 -(2-isopropoxyp heny1)- 1H-benzo kflimidazole HO
CI N n ir

133 (4-((cyclopropylmethyl)sulfonyl)phenyl)(5,7-dichloro-6-(2-isopropoxypheny1)-1H-benzokflimidazol-2-y1)methanol OH
CI N_NH
WP

134 =CI 134 2 -(4-((c ycloprop ylmethypsulfonyflpheny1)-2-(4,6-dichloro-5 -(2-isopropoxyp heny1)- 1H-benzo kflimidazo1-2-yflethanol OH
nj-CI 1\1...,NH=

0,0

135 ,0 CI 135 2 -(4-((c ycloprop ylmethypsulfonyflpheny1)-2-(4,6-dichloro-5 -(2-metho xypheny1)- 1H-benzo kflimidazo1-2- yflethanol a N..._NH 1111

136 4,6-dichloro-2-(4-((cycloprop ylmethyl)sulfonyflbenz y1)-5 -(2-ethoxyp heny1)-1H-benzo1dlimidazole OH
CI NI,NH g,0 v

137 CI 137 2-(4-((cyclopropylmethyl)sulfonyl)pheny1)-2-(4,6-dichloro-5-(2-ethoxypheny1)-1H-benzoldlimidazol-2-yl)ethanol HO
CI NI_NH=

138 ci 138 (4-((cyclopropylmethyl)sulfonyl)phenyl)(4,6-dichloro-5-(2-ethoxypheny1)-1H-benzoldlimidazo1-2-yl)methanol EtO2S
CI rt-F
N N
N " CI
o Et0 ethyl 3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-y1)-1H-benzokllimidazol-2-y1)-3-(4-(ethylsulfonyl)phenyl)propanoate Eto2s ci N 4111"1 CI
HO
3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-y1)-1H-benzoldlimidazol-2-y1)-3-(4-(ethylsulfonyl)phenyl)propan-1-ol Eto2s CI
/IV AI
N 1111111)11 Ol

139 HO

(S)-3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-y1)-1H-benzoldl imidazol-2-y1)-3-(4-(ethylsulfonyl)phenyl)propan-1-ol EtO2S
41, CI (i-F
N

140 ' N oi H

(R)-3-(4,6-dichloro-5-(4,4-difluoropiperidin-l-y1)-1H-benzokflimidazo1-2-y1)-3-(4-(ethylsulfonyl)phenyl) propan-l-ol oõp `SI
CI
\

141 FXF

3-(5-chloro-6-(2-(difluoromethoxy)pheny1)-1H-benzokflimidazo1-2-y1)-3-(4-((cyclopropylmethyl)sulfonyflphenyflpropanamide Aktik=ix CI

142 OH

F )F 142 3-(5-chloro-6-(2-(difluoromethoxy)pheny1)-1H-benzokflimidazo1-2-y1)-3-(4-((cyclopropylmethypsulfonyflphenyepropan-1-01 CI
\ 0

143 NH2 3-(5-chloro-6-(2-isopropoxypheny1)-1H-benzokflimidazo1-2-y1)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanamide o CI N

144 OH
:L. 144 3-(5-chloro-6-(2-isopropoxypheny1)-1H-benzokflimidazo1-2-y1)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propan-1-01 oõp µs¨\
F= CI

145 a N
OH

3 -(4,6-dichloro-5-(4,4-difluoropiperidin-1 - y1)-1H-benzo ldlimidazo1-2- y1)-(4-(ethylsulfonyl)phenyl)prop an-l-ol EtO2S
N OLF
CI

3 -(4,6-dichloro-5-(4,4-difluoropiperidin-1 - y1)-1H-benzo ldlimidazo1-2- y1)-(4-(ethylsulfonyl)phenyl)prop anamide Eto2s CI ri¨F

146 N IW CI

(S)-3 -(4 ,6-dichloro-5 -(4,4-difluoropip eridin-1- y1)-1H-b enzoldl imidazo1-2- y1)-3 -(4-(ethylsulfonyl)phenyeprop anamide EtO2S
CI ri¨F
IN Atli N IW CI

147 H

(R)-3 -(4,6-dichloro-5 -(4,4-difluoropiperidin-1- y1)- 1H-benzo ldlimidazo1-2-y1)-3 -(4-(ethylsulfonyl)phenyeprop anamide N a Et0 ethyl 3 -(6-chloro-5 -(2-isopropo xypheny1)-1H-b enzo [di imidazol -2- y1)-3 -(4-((cycloprop ylmethyl)sulfonyl)phenyl)prop anoate N CI

3-(6-chloro-5-(2-isopropoxypheny1)-1H-benzo[dlimidazo1-2-y1)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanamide

148 NCI
OH

(S)-3-(6-chloro-5-(2-isopropoxypheny1)-1H-benzo[dlimidazo1-2-y1)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanamide <L,

149 N CI

(R)-3-(6-chloro-5-(2-isopropoxypheny1)-1H-benzo[dlimidazo1-2-y1)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanamide N CI
HO
3-(6-chloro-5-(2-isopropoxypheny1)-1H-benzo[dlimidazo1-2-y1)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propan-1-01 =

150 ' N CI
H
HO

(R)-3-(6-chloro-5-(2-isopropoxypheny1)-1H-benzo[dlimidazo1-2-y1)-3-(4-((cyclopropylmethypsulfonyl)phenyepropan-1-01 <C¨go

151 N c1 HO

(S)-3-(6-chloro-5-(2-isopropoxypheny1)-1H-benzoldlimidazo1-2-y1)-3-(4-((cyclopropylmethypsulfonyflphenyepropan-1-01 FF

Et0 ethyl 3-(6-chloro-5-(2-(difluoromethoxy)pheny1)-1H-benzoldlimidazo1-2-y1)-3-(4-((cyclopropylmethyl)sulfonyflphenyl)propanoate <U)FF
d!
N CI

3-(6-chloro-5-(2-(difluoromethoxy)pheny1)-1H-benzoldlimidazol-2-y1)-3-(4-((cyclopropylmethyl)sulfonyflphenyl)propanamide FF

152 CI

(S)-3-(6-chloro-5-(2-(difluoromethoxy)pheny1)-1H-benzoldlimidazol-2-y1)-3-(4-((cyclopropylmethypsulfonyflphenyl)propanamide FF
O'

153 N CI

(R)-3-(6-chloro-5-(2-(difluoromethoxy)pheny1)-1H-benzoldlimidazol-2-y1)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanamide CI
0õ0 FFX S
CI N

154 NH2 3 -(4-((c ycloprop ylmethyl)sulfonyflpheny1)-3 -(5 ,7-dichloro-6-(4,4-difluoropiperidin- 1 - y1)- 1H-benzo 1dlimidazo1-2 - yl)propanamide FF

N CI
HO
3 -(6-chloro-5 -(2-(difluorometho xy)pheny1)- 1H-benzo1dlimidazo1-2- y1)-3 -(4 -((c ycloprop ylmethypsulfonyflphenyeprop an-1 -ol <Li) FF

155 CI

(S)-3 -(6-chloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo1dlimidazo1-2- y1)-3 -(4-((c yclopropylmethyl)sulfonyflphenyflpropan- 1-01 FF

156 H CI

(R)-3-(6-chloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo kflimidazo1-2- y1)-3 -(4-((c yclopropylmethyl)sulfonyflphenyflpropan- 1-01 CI

Cl N

157 3 -(4-((c ycloprop ylmethyl)sulfonyflpheny1)-3 -(5 ,7-dichloro-6-(4,4-difluoropiperidin- 1 - y1)- 1H-benzo kflimidazo1-2- yflpropan-l-ol \S/-\
il4/1"

158 3 -(4-((cyclopropylmethyl)sulfonyflpheny1)-3-(5,7-dichloro-6-(2-(difluoromethoxy)pheny1)-1H-benzo kflimidazo1-2-yl)propanamide µe-\
F)0CI

159 CI
OH

3 -(4-((cyclopropylmethypsulfonyflpheny1)-3-(5,7-dichloro-6-(2-(difluoromethoxy)pheny1)-1H-benzo kflimidazo1-2- yflprop an-l-ol CI
0õ0 FN N \S
CI
N
H r

160 OH

(S)-3-(4-((cyclopropylmethyl)sulfonyepheny1)-3-(5,7-dichloro-6-(4,4-difluoropiperidin-l-y1)-1H-benzo yl)prop an-1 -ol CI
F, /-MN
S
Cl N

161 OH

(R)-3-(4-((cyclopropylmethyl)sulfonyl)pheny1)-3 -(5,7 -dichloro-6-(4,4-difluoropiperidin-l-y1)-1H-benzo yl)prop an-1 -ol CI
,0 FF-CN N S
CI N
H

162 (S)-3-(4-((cyclopropylmethyl)sulfonyepheny1)-3-(5,7-dichloro-6-(4,4-difluoropiperidin-l-y1)-1H-benzokllimidazo1-2-y1)propanamide F CI
FN
0õ ,0 CI N

163 NH2 (R)-3-(4-((cyclopropylmethyl)sulfonyl)pheny1)-3 -(5,7 -dichloro-6-(4,4 -diflu oropiperidin-1 - y1)-1H-benzo yl)propanamide <c_g FF
W N
N

164 ,0 164 (S)-4-(3-(6-chloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo kllimidazo1-2- y1)-3 -(4-((cyclopropylmethyl)sulfonyl)phenyl)propyl)morpholine FF
Of0

165 H ci (R)-4-(3 -(6-chloro -5 -(2 -(difluoromethoxy)pheny1)- 1H-benzo kllimidazo1-2-y1)-3 -(4-((cyclopropylmethyl)sulfonyl)phenyl)propyl)morpholine ,s FF

166 HN
ch 166 (S)-N - (3 - (6 - chlo ro -5 -(2-(difluoromethoxy)pheny1)-1H-benzo y1)-3 -(4-((cyclopropylmethyl)sulfonyl)phenyl)propyl)acetamide FF

167 hi CI
HI\1_ 167 (R)-N - (3 -(6 - chlo r o - 5 -(2-(difluoromethoxy)pheny1)-1H-benzo y1)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propyl)acetamide FOC
\g"

168 o N-(3-(5-chloro-6-(2-(difluoromethoxy)pheny1)-1H-benzoldlimidazo1-2-y1)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propyl)acetamide

169 N¨\
169 c_oi 4-(3-(5-chloro-6-(2-(difluoromethoxy)pheny1)-1H-benzoldlimidazo1-2-y1)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propyl)morpholine ci 04,A
FF,>(--> =

170 170 Co 4-(3-(4-((cyclopropylmethyl)sulfonyflpheny1)-3-(5,7-dichloro-6-(4,4-difluoropiperidin-l-y1)-1H-benzo [di imid azol-2- yflprop yflmorpho line ci R \_< 0 W
FFC\IN N \S

171 N 0 N-(3-(4-((cyclopropylmethyl)sulfonyflpheny1)-3-(5,7-dichloro-6-(4,4-difluoropiperidin-l-y1)-1H-benzo [di imidazol-2- yflprop yflacetamide In another aspect, the present invention is directed to a compound of formula ( IA ), Ra Rsa R5b R3 1\1 krcm, Br 40 bINHo Rb 0 R6 ( IA ) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is an intermediate for the synthesis of the compound of formula ( I ), wherein:
a b Ra, Rb, R1¨R3, R5a, R5b, R6, R7 and n are as defined in formula ( I ) .
In another aspect, the present invention is directed to a compound of formula ( IC ) or formula ( ID ), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, Ra 0 R3 Ra\ R5a R5b R5a R5b (1R4)s (R7)n NH 0 I R4)S R3 4.10 rk2 NH Rb s--0 R1 Rb R2 0\ R6 ( IC ) ( ID ) wherein:
Ra and Rb is hydrogen;
ring A, Ri¨R4, R5a, R5b, R6, R7, n and s are as defined in formula ( I ).
In some embodiments of the present invention, in a compound of formula (IC) or formula (ID), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, ring A is selected from the group consisting of phenyl, 0-6 cycloalkyl and 5 or 6 member heteroaryl, preferably piperidinyl, phenyl, thienyl, furyl and pyridinyl.
Typical intermediate compounds of the present invention include, but are not limited to, the compounds listed in the following table.
Example Compound Name No.
,o os ci = N is Br CI
5 -bromo -4,6 -dichloro-2- (4- (ethylsulfo nyl)b enzy1)- 1H-b enzo lcll imidazole g(:) HN Br N CI
5-bromo-4,6-dichloro-2-(4-(ethylsulfony1)-2-fluorobenzy1)-1H-benzo[dlimidazo1e FNH p Br! /P

6-bromo-2-(4-(ethylsulfonyl)benzy1)-5,7-difluoro-1H-benzo[dlimidazo1e ,o ,s-i\J I* Br 5-bromo-2-(4-(ethylsulfonyl)benzy1)-4,6-dimethy1-1H-benzo[dlimidazo1e CI

gC31 HN 411 Br N CI
4-((5-bromo-4,6-dichloro-1H-benzokflimidazo1-2-y1)methyl)-N-cyclopropylbenzenesulfonamide > .0 Br N CI
5-bromo-6-chloro-2-(4-((cyclopropylmethyl)sulfonyl)benzy1)-1H-benzo[dlimidazole CI NH2 0.%1 N N
CI
OH

N-(6-amino-2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)pheny1)-2-(4-(ethylsulfonyl)pheny1)-3-hydroxypropanamide OH
0,p \
CI. N

N-(2-amino-3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)pheny1)-2-(4-(ethylsulfonyl)pheny1)-3-hydroxypropanamide F ;H2 N-(6-amino-2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)pheny1)-2-(4-((cyclopropylmethyl)sulfonyl)phenyeacetamide CI al ISC) CI
N-(2-amino-3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)pheny1)-2-(4-((cyclopropylmethyl)sulfonyl)phenyeacetamide Et0 CI
N N
EtO2S 0 ethyl 4-((6-amino-2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)phenyl)amino)-3-(4-(ethylsulfonyl)pheny1)-4-oxobutanoate CI ri-F
EtO2S 0H2N N
CI
Et0 ethyl 4-((2-amino-3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl)amino)-3-(4-(ethylsulfonyl)pheny1)-4-oxobutanoate Et0 =V'0 CI
ethyl 4-((4-amino-6-chloro-2'-isopropoxy-111,1'-bipheny11-3-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyflpheny1)-4-oxobutanoate o H2N
CI
Et0 ethyl 4-((5-amino-2-chloro-2'-isopropoxy-111,1'-bipheny11-4-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyflpheny1)-4-oxobutanoate F,TõF

Et0 ethyl 4-((4-amino-6-chloro-2'-(difluoromethoxy)-111,1'-bipheny11-3-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-4-oxobutanoate FrF

CI
Et0 ethyl 4-((5-amino-2-chloro-2'-(difluoromethoxy)-111,1'-bipheny11-4-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-4-oxobutanoate In another aspect, the present invention is directed to a process for preparing the compound of formula ( I ), comprising a step of coupling a compound of formula ( IA ) with a compound of formula ( IB ) under an alkaline condition in the presence of a catalyst to give the compound of formula ( I ):

Ra R5a R5b (Rzt)s Ra , R5a R5b :7) R3 N )n 0 G (Rzt)s R3 - N (R7) n .'l ----- A
a1 ----- A.
I
Br 41 b IN \ I s,,,0 ( IB ) CO 41 b I
N sp,0 \ D. µ
Rb is "=-= is ".., 0 R6 Rb 0 R6 ( IA ) ( I ) wherein:
OH
G is leaving group, preferably boronic acid or borate, and more preferably +4 OH or c).
a b ring A, ¨, ¨, Ra, Rb, R1 AZ4, R5a, R5b, R6, R7, n and s are as defined in formula ( I ) .
In another aspect, the present invention is directed to a process for preparing the compound of formula ( I ), comprising a step of cyclization of a compound of formula (IC) or (ID) to give the compound of formula (I):
Ra r, 1 m5a R5b ,-, Ra R5a R5b (R0s 0 r.,3 ,Ni .......)R7)n NH 0 Ra , R5a R5b (R7)n R3 (R4)s R3 N.,..
(R4) 0 s 0 , 1 0 co or Rb I

0 R6 , ,...--c-C) R1 k ,2 R1 Rb (IC) (ID) ( I ) wherein:
a b ring A, ¨, ¨, Ra, Rb, R1 AZ4, R5a, R5b, R6, R7, n and s are as defined in formula ( I ) .
In another aspect, the present invention is directed to a process for preparing the compound of formula ( II ), comprising a step of cyclization of a compound of formula ( IIC ) or formula (IID) to give the compound of formula ( II ):
Ra ,.
6a R5b I
R3 Raµ R5a R5b NH 0rs Ra, R5a R5b (R7)n R3 (R7)n R3 N. (R2)n N .., / -0 s I.- N
R2 NH rc or (R4) R Rb sr..0 rOR
b \ Rb 0 6 R1 lib 0 R6 R2 R1 (IIC) (IID) ( II ) wherein:
a b ¨ , ¨ , Ra, Rb, RP"R4, R5a, R5b, R6, R7, n and s are as defined in formula ( II ).

In another aspect, the present invention is directed to a process for preparing the compound of formula ( III ), comprising a step of cyclization of a compound of formula ( IIIC ) or formula (IIID) is subject to intramolecular reaction to give a formula ( III ):
R 5R a R5b Ra Ra, R5a R5b (R4)SC

R3 a, P7). r ( R4) '5a R5b (R7)n 411 N R3 (R7)n (R4)s in 0 bN
soN 0 0 R6 Rb sr.0 Rb Oil R6 Ri R, R2 Ri \ R6 R2 (IIIC) (IIID) (III ) , wherein:
a b ¨ , ¨, Ra, Rb, RiR4, R5a, R5b, R6, R7, n and s are as defined in formula ( III
) .
In another aspect, the present invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula ( I
), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
In another aspect, the present invention is directed to a method for inhibiting a retinoid-related orphan receptor gamma (RORy) in a subject, comprising administering to the subject a therapeutically effective amount of the compound of formula (I), or the tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or the pharmaceutically acceptable salt, solvate or prodrug thereof.
In another aspect, the present invention is directed to a method for treating a retinoid-related orphan receptor gamma (RORy) protein mediated disease or disorder in a subject, comprising administering to the subject a therapeutically effective amount of the compound of formula (I), or the tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
In another aspect, the present invention is directed to use of the compound of formula ( I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in the preparation of a medicament for inhibiting RORy.
In another aspect, the present invention is directed to use of the compound of formula ( I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in the preparation of a medicament for treating a RORy protein mediated disease or disorder.

In another aspect, the present invention further relates to a compound of the formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof for use as a medicament.
In another aspect, the present invention further relates to a compound of the formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof for use as a RORy inhibitor.
In another aspect, the present invention further relates to a compound of the formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof for use as a medicament for treating a RORy protein mediated disease or disorder.
RORy protein mediated diseases or disorders include, but are not limited to, inflammation and autoimmune diseases and cancers, wherein inflammation and autoimmune diseases include, but are not limited to, arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, osteoarthritis, regional entrritis, ulcerative colitis, ankylosing spondylitis, autoimmune diabetes, type I diabetes, autoimmune ocular disease, autoimmune thyroid disease, autoimmune polyedocrine syndrome type I, autoimmune polyendocrine syndrome type II, multiple sclerosis, inflammatory bowel disease, inflammatory bowel syndrome, juvenile idiopathic arthritis, Sjogren's syndrome, Crohn's disease, asthma, Kawasaki Disease, Hashimoto's thyroiditis, infectious diseases, ankylosing spondylitis, chronic obstructive pulmonary disease (COPD), pulmonary disease, glomerulonephritis, myocarditis, thyroiditis, dry eye, Uveitis, Behcet's disease, asthma, atopic dermatitis, contact dermatitis, allograft rejection, polymyocitis, grad versus host disease, acne, ulcerative colitis, systemic lupus erythemato sus, scleroderma, bronchitis, dermatomyositis and allergic rhinitis; and wherein cancers include, but are not limited to, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, synovial sarcoma, breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, melanoma, solid tumor, glioma, nerve Glioblastoma, hepatocellular carcinoma, mastoid renal tumor, head and neck tumor, leukemia, lymphoma, myeloma and non-small cell lung cancer.

DEFINITIONS
Unless otherwise stated, the terms used herein have the following meanings.
"Alkyl" refers to a linear or branched saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms, preferably C1-C12 alkyl, more preferably C1-C6 alkyl, sometimes more preferably C1-C4 alkyl. Nonlimiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylprop yl, 1 -ethylprop yl, 2-methylbutyl, 3 -methylbu tyl, n-hexyl, 1 -ethy1-2-methylprop yl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and the branched isomers thereof. More preferably an alkyl group is a lower alkyl having 1 to 6 carbon atoms, and the nonlimiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylprop yl, 1,1,2-trimethylpropyl, 1,1 -dimethylb utyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group can be substituted or unsubstituted. When substituted, the substituent group(s) can be substituted at any available connection point. The substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocylic alkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxyl, and carboxylic ester.
"Alkylene" refers to a hydrogen atom of an alkyl which is further substituted.
For example, methylene(-CH2-), 1,2-ethylene(-CH2CH2-), 1,3-propylene(-CH2CH2CH2-), 1,4-butylene(-CH2CH2CH2CH2-), and the like.
"Alkenyl" refers to an alkyl defined as above that has at least two carbon atoms, preferably 2-10 carbons, more preferably 2-6 carbons, sometimes more preferably 2-4 carbons, and at least one carbon-carbon double bond, for example, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl and the like. The alkenyl group may be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyl, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocyclylthio.
"Cycloalkyl" refers to a saturated and/or partially unsaturated monocyclic or polycyclic hydrocarbon group having 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and most preferably 3 to 6 carbon atoms.
Nonlimiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like. Polycyclic cycloalkyl includes a cycloalkyl having a spiro ring, fused ring or bridged ring.
"Spiro cycloalkyl" refers to a 5 to 20 membered polycyclic group with rings connected through one common carbon atom (called a spiro atom), wherein one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system, preferably 6 to 14 membered spiro cycloalkyl, and more preferably 7 to 10 membered spiro cycloalkyl. According to the number of the common spiro atoms, spiro cycloalkyl may be divided into mono-spiro cycloalkyl, di-spiro cycloalkyl, or poly-spiro cycloalkyl, and preferably a mono-spiro cycloalkyl or di-spiro cycloalkyl, more preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered mono-spiro cycloalkyl.
Nonlimiting examples of spiro cycloalkyls include, but are not limited to:
EW7 ____________________________________________________ and =
"Fused cycloalkyl" refers to a 5 to 20 membered full-carbon polycyclic group, wherein each ring in the system shares an adjacent pair of carbon atoms with another ring, wherein one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system, preferably 6 to 14 membered fused cycloalkyl, more preferably 7 to 10 membered fused cycloalkyl. According to the number of membered rings, fused cycloalkyl may be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic, tricyclic or tetracyclic fused cycloalkyl, and more preferably bicyclic or tricyclic. Nonlimiting examples of fused cycloalkyl include, but are not limited to:

and "Bridged cycloalkyl" refers to a 5 to 20 membered full-carbon polycyclic group, wherein every two rings in the system share two disconnected atoms, wherein the rings may have one or more double bonds, but none of the rings has a completely conjugated pi-electron system, preferably 6 to 14 membered bridged cycloalkyl, and more preferably 7 to 10 membered bridged cycloalkyl. According to the number of membered rings, bridged cycloalkyl may be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, and preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyl, and more preferably bicyclic or tricyclic bridged cycloalkyl. Nonlimiting examples of bridged cycloalkyls include , but are not limited to:
7h.µ
k4 and isg-t-Said cycloalkyl include above cycloalkyl fused to aryl, heteroaryl or heterocyclyl, wherein the ring bound to the parent structure is cycloalkyl. Nonlimiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl and the like. The cycloalkyl may be optionally substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more group(s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocylic alkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxyl, carboxylic ester.
"Heterocycly1" refers to a 3 to 20 membered saturated and/or partially unsaturated monocyclic or polycyclic hydrocarbon group having one or more heteroatoms selected from the group consisting of N, 0, and S(0)m (wherein m is an integer selected from 0 to 2) as ring atoms, but excluding -0-0-, -0-S- or -S-S- in the ring, and the remaining ring atoms being carbon atoms. Preferably, heterocyclyl has 3 to 12 atoms with 1 to 4 heteroatoms, more preferably 3 to 6 atoms. Nonlimiting examples of monocyclic heterocyclyl include, but are not limited to, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like. Polycyclic heterocyclyl .. includes a heterocyclyl having a spiro ring, fused ring or bridged ring.
"Spiro heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclyl with rings connected through one common atom (called a spiro atom), wherein said rings have one or more heteroatoms selected from the group consisting of N, 0, and S(0)m (wherein m is an integer selected from 0 to 2) as ring atoms and the remaining ring atoms being carbon atoms, wherein one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system; preferably 6 to 14 membered spiro heterocyclyl, and more preferably 7 to 10 membered spiro heterocyclyl. According to the number of common spiro atoms, spiro heterocyclyl may be divided into mono-spiro heterocyclyl, di-spiro heterocyclyl, or poly-spiro heterocyclyl, preferably mono-spiro heterocyclyl or di-spiro heterocyclyl, and more preferably 4-membered/4-membered, 4-membered/5 -membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered mono-spiro heterocyclyl. Nonlimiting examples of spiro heterocyclyls include, but are not limited to:
-1,An cN)414 N
N Ill 0 0 S 0 or 41 "Fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclyl group, wherein each ring in the system shares an adjacent pair of atoms with another ring, wherein one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system, and wherein said rings have one or more heteroatoms selected from the group consisting of N, 0, and S(0)m (wherein m is an integer selected from 0 to 2) as ring atoms, and the remaining ring atoms being carbon atoms;
preferably 6 to 14 membered fused heterocyclyl, and more preferably 7 to 10 membered fused heterocyclyl. According to the number of membered rings, fused heterocyclyl may be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl, preferably bicyclic or tricyclic fused heterocyclyl, and more preferably 5-membered/5-membered, or 5-membered/6-membered bicyclic fused heterocyclyl. Nonlimiting examples of fused heterocyclyl include, but are not limited to:

N y,90 1"`M .141C
01\111.4 1¨ciN >7-1 8 8 and "Bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclyl group, wherein every two rings in the system share two disconnected atoms, wherein the rings may have one or more double bonds, but none of the rings has a completely conjugated pi-electron system, and the rings have one or more heteroatoms selected from the group consisting of N, 0, and S(0)m (wherein m is an integer selected from 0 to 2) as ring atoms, and the remaining ring atoms being carbon atoms; preferably 6 to 14 membered bridged heterocyclyl, and more preferably 7 to 10 membered bridged heterocyclyl. According to the number of membered rings, bridged heterocyclyl may be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, and preferably bicyclic, tricyclic or tetracyclic bridged heterocyclyl, and more preferably bicyclic or tricyclic bridged heterocyclyl. Nonlimiting examples of bridged heterocyclyls include, but are not limited to:
kp-t _________ Vcz' andt Said heterocyclyl includes above heterocyclyl fused to aryl, heteroaryl or cycloalkyl, wherein the ring bound to the parent structure is heterocyclyl. Nonlimiting examples include, but are not limited to:

0 0 N and , etc.
The heterocyclyl may be optionally substituted or unsubstituted. When substituted, the 20 substituent group(s) is preferably one or more group(s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocylic alkoxy, cycloalkylthio, heterocylylthio, oxo, carboxyl, carboxylic ester.

"Aryl" refers to a 6 to 14 membered full-carbon monocyclic ring or polycyclic fused ring (i.e.
each ring in the system shares an adjacent pair of carbon atoms with another ring in the system) group having a completely conjugated pi-electron system; preferably 6 to 10 membered aryl, more preferably phenyl and naphthyl, and most preferably phenyl. The aryl includes above aryl fused to heteroaryl, heterocyclyl or cycloalkyl, wherein the ring bound to parent structure is aryl. Nonlimiting examples include, but are not limited to:
111L c) s Ok =

N H
N H
wi=, 0 .
N. * N 0 0 110 0 0 <N 40 H H H
N N N
, ---e N = Nix . I and 01 /
N s N 0 c) =
, H
N
e N
preferably .
.. The aryl may be optionally substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocylic alkoxy, cycloalkylthio, heterocyclylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, and carboxylic ester.
"Heteroaryl" refers to 5 to 14 membered aryl having 1 to 4 heteroatoms selected from the group consisting of 0, S and N as ring atoms and remaining ring atoms being carbon atoms; preferably 5 to 10 membered heteroaryl, more preferably 5- or 6-membered heteroaryl such as imidazolyl, furyl, thienyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, and the like, preferably imidazolyl, pyrazolyl, pyimidinyl or thiadiazole; more preferably pyrazolyl. The heteroaryl includes above heteroaryl fused to aryl, heterocyclyl or cycloalkyl, wherein the ring bound to parent structure is heteroaryl.
Nonlimiting examples include, but are not limited to:
OC
NI. H N01 ..---H H
Y\ 1$1 N and ; preferably N .

The heteroaryl may be optionally substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocylic alkoxy, cycloalkylthio, heterocyclylthio, carboxyl, and carboxylic ester.
"Alkoxy" refers to an -0-(alkyl) or an -0-(unsubstituted cycloalkyl) group, wherein the alkyl is as defined above. Nonlimiting examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. The alkoxy may be optionally substituted or unsubstitutecl. When substituted, the substituent is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocylic alkoxy, cycloalkylthio, heterocyclylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, and carboxylic ester.
"Haloalkyl" refers to an alkyl substituted with one or more halogen, wherein alkyl is as defined above.
"Haloalkoxy" refers to an alkoxy substituted with one or more halogen, wherein alkoxy is as defined above.
"Hydroxyalkyl" refers to an alkyl substituted with hydroxy, wherein alkyl is as defined above.
"Hydroxy" refers to an -OH group.
"Halogen" refers to fluorine, chlorine, bromine or iodine.
"Amino" refers to an ¨NH2 group.
"Cyano" refers to a -CN group.
"Nitro" refers to an ¨NO2 group.
"Oxo" refers to =0.
"Carboxyl" refers to a -C(0)0H group.
"Carboxylic ester" refers to a -C(0)0(alkyl) or -C(0)0(cycloalkyl) group, wherein the alkyl and cycloalkyl are as defined above.
"Optional" or "optionally" means that the event or circumstance described subsequently can be, but need not be, and such descriptions include the situation in which the event or circumstance may or may not occur. For example, "the heterocyclic group optionally substituted with an alkyl" means that an alkyl group can be, but need not be, present, and such description includes the situation of the heterocyclic group being substituted with an alkyl and the heterocyclic group being not substituted with an alkyl.
"Substituted" refers to one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently substituted with a corresponding number of substituents. It goes without saying that the substituents only exist in their possible chemical position. The person skilled in the art is able to determine whether the substitution is possible or impossible by experiments or theory without paying excessive efforts. For example, when amino or hydroxy with free hydrogen is bound to a carbon atoms having unsaturated bonds (such as olefinic) may be unstable.
For any substituents alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl, c ycloalkoxy, heterocylic alkoxy, c ycloalkylthio , heterocyclylthio, and carboxylic ester mentioned throughout the application, any alkyl is preferably Ci-C6 alkyl, sometimes more preferably Ci-C4 alkyl; any alkenyl is preferably C2-C6 alkenyl, sometimes more preferably Ci-C4 alkenyl; any alkynyl is preferably alkynyl, sometimes more preferably Ci-C4 alkynyl; any cycloalkyl is preferably cycloalkyl; any heterocyclyl is preferably 5- to 10-membered, sometimes more preferably 5-or 6-membered heterocyclyl; any aryl is preferably C6-C10 aryl, more preferably phenyl; any heteroaryl is 5- to 10-membered, sometimes more preferably 5- or 6-membered, heteroaryl;
and any carboxylic ester is preferably Ci-C4 alkyl ester, sometimes more preferably methyl or ethyl ester.
A "pharmaceutical composition" refers to a mixture of one or more of the compounds according to the present invention or physiologically/pharmaceutically acceptable salts or prodrugs thereof and other chemical components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism and the absorption of the active ingredient and thus displaying biological activity.
The compounds of the present disclosure can exist as pharmaceutically acceptable salts or solvates. Pharmaceutically acceptable salts may be any acid addition salt formed by a compound of formula I and a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, malonic, mandelic, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid, or the like.
"Solvate" refers to a physical association of a compound of this invention with one or more, preferably one to three, solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example, when one or more, preferably one to three, solvent molecules are incorporated in the crystal lattice of the crystalline solid. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates.
Methods of solvation are generally known in the art.
"Therapeutically effective amount" refers to the total amount of each active component that is sufficient to show a meaningful patient benefit, e.g., a sustained reduction in viral load.
When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially, or simultaneously.
"Pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
"Patient" or "subject" includes both human and other mammalian animals, including but not limited to cats, dogs, cows, horses, or the like.
"Treating" or "treatment" refers to: (i) inhibiting the disease, disorder, or condition, i.e., arresting its development; and (ii) relieving the disease, disorder, or condition, i.e., causing regression of the disease, disorder, and/or condition. In some embodiments, the present invention also includes use of a compound according to any embodiment disclosed for preventing a disease, disorder or condition from occurring in a patient that may be predisposed to the disease, disorder, and/or condition but has not yet been diagnosed as having it;
Any terms in the present application, unless specifically defined, will take the ordinary meanings as understood by a person of ordinary skill in the art. All references cited herein are incorporated by reference in their entireties.
SYNTHESIS METHOD OF THE PRESENT INVENTION
In order to obtain the object of the present invention, the present invention applies the following synthetic technical solutions:
A process for preparing a compound of formula ( I ) of the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the following steps:

Scheme 1 o p (RAI vr. s6 b.:'0 R3 (R7) 0n ji, R6 R3 (R7)n g- R6 R3 0 X NH2 0 \ \ bc) X N H2 \ ---... .4.--0 x HN
W + HO I ..-- Step 1 0 0 1 , 0 R5a R5b R2 NH2 R2 N or R2 R 1 R5a R5a R 1 H
R5a R5b R 1 ( 1-1 ) ( 1-2 ) ( 1-3 ) (1-3. ) Ra \ R5a R5b (Ra)s Ra, R5a R5b ¨G _ (KAI
I C) R3 N'?b'1 Step 2 X 41 b 1 \ s,0 (IB) (IR4)scp ___________________________________ ... µ
Po.
Rb (s R6 Step 3 Rb u ¨6 ( IA ) ( I ) Step 1, the compound of the formula ( I-1 ) is subjected to a condensation reaction with formula ( 1-2 ) under alkaline conditions to obtain a compound of the formula ( 1-3 ) or formula ( I-3') ;
Step 2, the formula ( 1-3 ) or formula (1-3') is subjected to an intramolecular reaction in the presence of an acid to give a compound of the formula ( IA );
Step 3, the compound of formula ( IA ) is subject to coupling reaction with formula ( IB ) under an alkaline condition in the presence of catalyst to give a formula ( I );
wherein:
X is halogen, preferably bromine;
,OH

G is leaving group, preferably boronic acid or borate; more preferably OH
or a b ring A, ¨, ¨, Ra , Rb, R1¨R4, R5a, R5b, R6, R7, n and s are as defined in formula ( I ).
Alkaline reagents include organic base and inorganic base, wherein said organic base includes, but is not limited to, triethylamine, N,N-disopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide or potassium tert-butwdde, wherein said inorganic base includes, but is not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate or cesium carbonate.
Phosphine palladium-based catalysts include, but are not limited to, 2-(dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl, ( )-2,2'-bis(diphenylphosphino) -1,1 -binaphthyl, tris(dibenzylideneacetone)dipalladium(0), palladium diacetate, 111,1 '-bis (diphenylp ho sphino)ferro cenel dichlorop alladium, triphenylphosphine and tetrakis (triphenylpho sphine)p all adium.
The above reactions are preferably carried out in a solvent. The solvent used includes, but is not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, and mixtures thereof.
A process for preparing a compound of formula ( I ) of the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the following steps:
Scheme 2 R5a R5b Ra R5a R5b (R,)b R3 R R5a R5b NH2 0 (R7)n R3 (R7)n (1R4)s R3 \
(R7), Rb 5 op (1R4)s Nµi CO b a 410 ,0 0 -.0 or 17C

IR) 0 ( IC ) ( ID) ( I ) The formula ( IC ) or formula ( ID) is subjected to an intramolecular reaction in the presence of an acid to give a compound of the formula ( I );
wherein:
a b ring A, ¨, ¨, Ra , Rb, Ri-R4, R5a, R5b, R6, R7, n and s are as defined formula ( I ).
The reagents that provide an acidic condition include, but are not limited to, acetic acid, pyridine hydrobromide, trifluoroacetic acid, formic acid, hydrochloric acid, sulfuric acid and methanesulfonic acid, preferably pyridine hydrobromide or hydrochloric acid.
The above reactions are preferably carried out in a solvent. The solvent used includes, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, and mixtures thereof.
A process for preparing a compound of formula ( II) of the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the following steps:

Scheme 3 Ra I R56 R5b m Ra R5a R5b NH 0 Ra, R5a R5b (R4)s = r<3 \ (R7)a R3 (R7)n R3 N
(R7)n 0 N I o I
or (R4)s, N b R2 NH , 1 R6 R2 RI io \ Rb 0 6 R1 Rb 8 0 R6 R2 R1 (IIC) ( IID ) ( II ) The formula ( IIC ) or formula ( IID) is subjected to an intramolecular reaction in the presence of an acid to give a compound of the formula ( II );
wherein:
a b ¨, ¨, Ra , Rb, R1-R4, R5a, R56, R6, R7, n and s are as defined in formula ( II
).
The reagents that provide an acidic condition include, but are not limited to, acetic acid, pyridine hydrobromide, trifluoroacetic acid, formic acid, hydrochloric acid, sulfuric acid and methanesulfonic acid, preferably pyridine hydrobromide or hydrochloric acid.
The above reactions are preferably carried out in a solvent. The solvent used includes, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, and mixtures thereof.
A process for preparing a compound of formula ( III ) of the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the following steps:
Scheme 3 R R5a R5b Ra (R4)sse R3 aµ \ (R7)a I R6a R5b 1.-\__ Ra \ R5a R5b (R7)n N // NH 0 R3 N.
R3 (R7)n (R4)s)C¨\,N 0 1 it b s,,c0 or (R4)s,N ilk Nµ N

Ri II, 05 R6 R1 Rb Fr\-0 R2 RI Rb 0 6 (IIIC) ( IIID ) ( III ) The formula ( IIIC ) or formula ( IIID) is subjected to an intramolecular reaction in the presence of an acid to give a compound of the formula ( III );
wherein:
a b ¨, ¨, Ra , Rb, R1¨R4, R5a, R56, R6, R7, n and s are as defined formula ( III
).
The reagents that provide an acidic condition include, but are not limited to, acetic acid, pyridine hydrobromide, trifluoroacetic acid, formic acid, hydrochloric acid, sulfuric acid and methanesulfonic acid, preferably pyridine hydrobromide or hydrochloric acid.
The above reactions are preferably carried out in a solvent. The solvent used includes, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, and mixtures thereof.
The present invention will be further described with the following examples, but the examples should not be considered as limiting the scope of the invention.
EXAMPLES
The structures of the compounds were identified by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR was determined by a Bruker AVANCE-400 or AVANCE III 500. The solvents are deuteratecl-dimethyl sulfoxide (DMSO-d6), deuterated-chloroform (CDC13) and deuterated-methanol (CD30D) with tetramethylsilane (TMS) as an internal standard. NMR chemical shifts (5) are given in 10-6 (ppm).
High performance liquid chromatography (HPLC) was determined on an Agilent 1200DAD high pressure liquid chromatography spectrometer (Sunfire C18 150x4.6 mm chromatographic column) and a Waters 2695-2996 high pressure liquid chromatography spectrometer (Gimini C18 150x4.6 mm chromatographic column).
Chiral high performance liquid chromatography (HPLC) was determined on LC-10A vp (Shimadzu)or SFC-analytical (Berger Instruments Inc.) MS was determined by a SHIMADZU (ESI) liquid chromatography-mass spectrometer (manufacturer: Shimadzu, type: LC-20AD, LCMS-2020).
The known raw materials of the present invention were prepared by the conventional synthesis methods in the art, or purchased from Aldrich Chemical Company, Fisher Scientific or Combi-Blocks, etc.
Unless otherwise stated, the reactions were carried out under nitrogen atmosphere or argon atmosphere.
The term "nitrogen atmosphere" or "argon atmosphere" means that a reaction flask was equipped with a 1 L nitrogen or argon balloon.
The term "hydrogen atmosphere" means that a reaction flask was equipped with a hydrogen balloon.
Unless otherwise stated, the reaction temperature in the reactions refers to room temperature, and the range of the temperature was 20 C to 30 C.
The reaction process was monitored by thin layer chromatography (TLC), and the developing solvent system includes: A: dichloromethane and methanol, B: hexane and ethyl acetate. The ratio of the volume of the solvent was adjusted according to the polarity of the compounds. The elution system for purification of the compounds by column chromatography, thin layer chromatography and CombiF/ash flash rapid preparation instrument includes: A: dichloromethane and methanol, B: hexane and ethyl acetate. The ratio of the volume of the solvent was adjusted according to the polarity of the compounds, and sometimes a small amount of basic reagent such as ammonia or acidic reagent such as .. acetic acid was added.
Final compounds were purified by Shimadzu (LC-20AD, SPD20A) Prepative HPLC
(Phenomenex Gemini-NX 5uM C18 21.2x100mm column) with an elution system: C:
0.075% TFA in water and 0.075% TFA in Me0H or D: 0.075% TFA in water and 0.075%
TFA in CH3CN.
The following abbreviations are used:
TEA is triethylamine, DIPEA is N,N-diisopropylethylamine, EDCI is N-(3-Dimethylaminopropy1)-N'-ethylcarbodiimide hydrochloride, HOBt is 1-Hydroxybenzotriazole hydrate, .. DCM is dichloromathene, HBTU is 0-(Benzotriazol-1-y1)-N,N,M,N1-tetramethyluronium hexafluorophosphate, DMF is N,N-dimethylformamide, NMR is proton nuclear magnetic resonance, and MS is mass spectroscopy with (+) referring to the positive mode which generally gives a M+1 (or M+H) absorption where M = the molecular mass.
Prep HPLC is Prepative High performance liquid chromatography.
Example 1 Preparation of 4,6-dichloro-2-(4-(ethylsulfonyflbenzy1)-5-phenyl-1H-benzo [di imidazole o's CI
CI

i cH2a2 ',O
1 KOH/Me0H HO 40 ....-HO
0 SH K2CO3/DMF S 0 MCPBA g----, 2 HCI
111111)11 8 8 No, 02N 40 CI HNO3 02N 0 CI SnCl2 H2N 40 CI _/ 0 0 OH
Br H2SO4 02N Br Et0H H2N Br CI CI CI EDCl/HOBt/ DMF
,01-1 LP 0-'S' OH
(:) , 0 0H2N 13 Br Pd2(dbaP-Bu3)PHIBF4 * 0 CI HOAc _.. = CI )3, CI
reflux N Br aq Na2CO3, dioxane N
N
H
CI
N irCI N CI

Step 1. Preparation of ethyl 2-(4-(ethylthio)phenyl)acetate /. I
H = 0 0 401 K2CO3/DM F 0 (01 SH S
To a solution of 2-(4-mercaptophenyl) acetic acid (3.4 g, 0.02 mol) in N,N-dimethylformamide (DMF) (20 ml) was added K2CO3 (11 g, 0.04 mol) and iodoethane (6.4 g, 0.06 mol). The reaction mixture was stirred at RT. After 2,5 hours, the starting material was totally consumed. The reaction mixture was partitioned between ethyl acetate (30 ml) and water (30 m1). The organic phase was washed with water (30 ml) and brine (20 ml), dried over sodium sulphate, filtered, and concentrated to give the desired product ethyl [4-(ethylthio)phenyll acetate (3.6 g, 80%) as a pale yellow solid, MS (+) ES:
225(M+H) .
Step 2. Preparation of ethyl 2-(4-(ethylsulfonyl)phenyl)acetate _________________________________________ BP 1101 0 I I ,......, 0 1101 M CP BA 0 S" ' To a 250 ml round bottom flask, were added ethyl 2-(4-(ethylthio)phenyl)acetate (5.5 g, 0.0245 mol) and dichloromethane (82.5 m1). The reaction mixture was cooled to 0 C. To the same flask, m-chloroperbenzoic acid (12.6 g, 0.073 mol) was added at 0 C.
The reaction mixture was stirred at room temperature for 12 h. The resulting suspension was filtered through a pad of celite. The filtrate was washed with water. The organic layer was separated, washed with saturated sodium bicarbonate solution followed by brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by flash column chromatography with hexane/ethyl acetate to get the title compound as an oil that was solidified upon standing (4.7 g, 75%), MS (+) ES: 257 (M+H) .
Step 3. Preparation of 2-(4-(ethylsulfonyl)phenyl)acetic acid 1. KOH/Me0H HO

2. HCI 0 To a 50 mL round bottom flask, were added ethyl 2-(4-(ethylsulfonyl)phenyl)acetate (2.56 g, 0.01 mol) and ethanol ( 18 m1). To the same flask, a solution of sodium hydroxide in water (1.42 g, 0.0355 mol in 18 ml of water) was added. The reaction mixture was stirred at room temperature for 12 h. The volatiles were evaporated under reduced pressure. The residue was acidified with IN HC1 to pH 5.0 and extracted with ethyl acetate (15 ml X3). The organic layer was separated and combined, washed with brine and dried over sodium sulfate.
The solvent was evaporated under reduced pressure to get the title compound as a colorless oil that was solidified upon standing (2.0 g, 85%), MS (+) ES: 229 (M+H) Step 4. Preparation of 2 -bro mo-1 ,3 -dichloro-4 ,5-dinitrobenzene 02 *CI HNO3 02N * CI
Br H2SO4 02N Br I Cl 2-bromo-1,3-dichloro-5-nitrobenzene (2.7 g, 0.01 mol) was carefully added into a pre-prepared solution of fuming nitric acid (10 ml) and concentrated sulfuric acid (10 ml) with stirring. After the addition, the mixture was heated to 50 C in a water bath for two hours until the completion of the reaction (LCMS monitor). The mixture was then cooled and poured onto ice. The yellow precipitate was collected by filtration and washed thoroughly with water and dried to afford the product as a yellow solid (3 g, 95%), MS (+) ES:
314 (M+H) .
Step 5. Preparation of 4 -bro mo-3 ,5 -dichlorob enzene- 1 ,2 -diamine 02N CI H2N * CI
02N Br H2N Br CI CI
To a stirred mixture of AcOH (50 ml) and Et0H (100 ml) was suspended 2-bromo-1,3-dichloro-4,5-dinitrobenzene (3.1 g, 0.01 mol) and iron powder (4.4 g, 0.08 mol). The reaction mixture was heated slowly to a gentle reflux and allowed to stir for 1 hour. The reaction mixture then was cooled to room temperature, diethyl ether (50 ml) and water (50 ml) were added. The solution was carefully neutralized by the addition of solid sodium carbonate. The organic phase was separated and the water phase was extracted with ethyl acetate (20 ml). The organic phases were combined and washed with saturated NaHCO3 (2.x.30 ml), H20 (2.x.30 ml) and brine (1.x.30 ml), then dried over MgSO4, filtered and concentrated to dryness under vacuum to yield the title compound as a off-white solid (2.0 g, 78%), MS (+) ES: 255 (M+H) .
Step 6. Preparation of N-(6-amino-3-bromo-2,4-dichloropheny1)-2-(4-(ethylsulfonyflphenyl)acetamide H2N a Olt = 2 ________________________________________ V. 0 H2N Br Br =
CI ED CI, HOBt/ DM F
CI
1-Ethyl-(3-(3-dimethylamino)propy1)-carbodiimide hydrochloride (2.0 g, 0.01 mol) and benzotriazol- 1 -ol (1.35 g, 0.01 mol) were added into a cooled solution (ice water bath) of 4-bro mo -3 ,5 -dichlorobenzene- 1 ,2-diamine (2.55 g, 0.01 mol) .. and .. 2-(4-(ethylsulfonyl)phenyl)acetic acid (step 3, 2.28 g, 0.01 mol) in DMF (10 ml), portionwise, over 30 mm. After the addition was completed, the mixture was stirred for 60 mm and was allowed to warm-up to room temp, stirred overnight. The mixture was partitioned between water (50 ml) and ethyl acetate (50 m1). The organic phase was separated and dried over MgSO4, filtered. The solvent was evaporated under reduced pressure to leave a off-white solid which was purified by flash chromatography with hexane/ethyl acetate to afford the product as a off-white solid (3.5 g, 75%), MS (+) ES: 466 (M+H) .
Step 7. Preparation of 5 -bro mo-4,6-dichloro-2 -(4-(ethylsu lfonyl)benz y1)-benzo dIimidazole ¨\ .0 o's 0H2N CI HOAc 41/ CI
/NI Br Br reflux C
CI I
N-(6-amino-3 -bro mo -2,4 -dichloropheny1)-2- (4 -(ethylsulfo nyflphenyl) acetamide(step 6) (3.5 g, 0.0075 mol) was mixed with acetic acid (25 ml) and the mixture was heated to 100 C for 4 hours, cooled. The solvent was evaporated under reduce pressure and the residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate, dried over MgSO4. This product was purified by flash chromatography with hexane/ethyl acetate to afford the product as a white solid (2.7 g, 80%), MS (+) ES: 448 (M+H) .
Step 8. Preparation of 4,6-dichloro-2-(4-(ethylsulfonyl)benzy1)-5-pheny1-1H-benzo dIimidazole ,o o's o's ci N 401 Br Pd2(dba)3, [(t-Bu3)PHP 411 / CI
aq. Na2CO3, dioxane CI NCI

A mixture of 5-bromo-4,6-dichloro-2-(4-(ethylsulfonyl)benzy1)-1H-benzoldlimidazole (step 7) (448 mg, 1 mmol), phenylboronic acid (363 mg, 3 mmol), tris-(dibenzylideneacetone)dipalladium(0) (60 mg), tri(tert-butyl)phosphonium tetrafluoroboronate (60 mg) and sodium carbonate (2M solution) in 1,4-dioxane (3 ml) was degassed, sealed and heated to 100 C under Microwave irradiation for lh. The volatile solvents were removed under reduced pressure. The residue was directly loaded onto a ISCO
solid cartridge and flashed with hexane/ethyl acetate to afford a white solid product 320 mg (72% yield), MS (+) ES: 445 (M+H) .
Example 2 Preparation of (4,6-dichloro-5-pheny1-1H-benzo [di imidazol-2-y1)(4-(ethylsulfonyl)phenyl)methanol ,o o's CI
HO N CI

Step 1. Preparation of (4,6-dichloro-5-pheny1-1H-benzo ldlimidazol-2-y1)(4-(ethylsulfonyl)phenyl)methanone ,o o o-s Mn02 ill 01 00 1,4 10-dioxane * N 161 4,6-dichloro-2-(4-(ethylsulfonyl)benzy1)-5-phenyl-1H-benzokllimidazole (example 1) (4.5 mg, 0.01 mmol) was dissolved in 1,4-dioxane (0.5 ml), Mn02 (5 mg, 0.058 mmol) was added at room temp. The mixture was stirred and heated to 60 C for 60 mm until the completion (LCMS monitor). After cooling, the solid was filtered off and the product was purified by flash chromatography with hexane/ethyl acetate to afford a white solid (4 mg.
87%), MS (+) ES: 459 (M+H) .
Step 2. Preparation of (4,6-dichloro-5-pheny1-1H-benzoldlimidazol-2-y1)(4-(ethylsulfonyflphenyl)methanol -o ¨X -o s- s-CI NaBF14 CI
Methanol 0 N CI HO N Cl (4,6-dichloro-5-pheny1-1H-benzokllimidazol-2-y1)(4-(ethylsulfonyl)phenyl)methanone (example 3, stepl) (4 mg, 0.0087 mmol) was dissolved in methanol (0.5 ml), sodium borohydride (1.6 mg, 0.044 mmol) was added and the mixture was stirred for 30 mm until completion. The product was purified by Prep HPLC with elution system C to afford a white solid (3.3 mg, 82%), MS (+) ES: 461 (M+H) .
Example 3 Preparation of 4,6-dichloro-2-(4-(ethylsulfonyl)benzy1)-5-(2-(trifluoromethyflphenyl)-1 H-benzoldlimidazole ,0 o's CI

In accordance with the synthetic route of example 1, the starting material, phenylboronic acid in step 8 was replaced with 2-trifluoromethylphenylboronic acid, accordingly, the title compound was obtain as a white solid, MS (+) ES: 513 (M+H) .
Example 4 Preparation of 2-(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzokllimidazol-2-y1)-2-(4-(ethylsulfonyl)phenyl)ethanol -o s-CI
HO a OCF3 ¨\ .0 s' N Na0Et/DMS0 CI
/
N 1=W ci OCF3 O HO N CI OCF3 4,6-dichloro-2-(4-(ethylsulfonyl)benzy1)-5-(2-(trifluoromethoxy)phenyl)-1H-benzoldlimidazole (5.3 mg, 0.01 mmol) was dissolved in 0.1 ml anhydrous DMSO, paraformylaldehyde (0.6 mg, 0.02 mmol) wan added with stirring, followed by the addition of powder sodium ethwdde (1.2 mg, 0.02 mmol). The mixture was stirred at room temp for 60 mm. The mixture was treated with small amount of diluted HC1 and directly purified by Prep HPLC with elution system C to afford the product as a white solid (3.8mg, 70% yield), MS (+) ES: 559 (M+H) .
Example 5 Preparation of (4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzokllimidazol-2-y1)(4-(ethylsulfonyl)phenyl)methanol ¨\ -0 CI

.. This product was prepared by essentially the same method as of example 2 to afford the product as a white solid, MS (+) ES: 545 (M+H) .
Example 6 Preparation of 2-(4,6-dichloro-5-(2-methoxypheny1)-1H-benzokllimidazol-2-y1)-2-(4-(ethylsulfonyl)phenyl)ethanol -o o's CI

o o CI
Na0ET/DMS0 0' _________________________________________ 11) CI
/NI r&

HO CI
This compound was prepared by essential the same method as of example 4 to afford the product as a white solid, MS (+) ES: 505 (M+H) .
Example 7 Preparation of (4,6-dichloro-5-(2-methoxypheny1)-1H-benzokllimidazol-2-y1)(4-(ethylsulfonyl)phenyl)methanol ¨\ .0 o CI

HO N CI

This product was prepared by essentially the same method as of example 2 to afford the product as a white solid, MS (+) ES: 491 (M+H) .
Example 8 Preparation of 4,6-dichloro-2-(4-(ethylsulfonyl)benzy1)-5-(2-isopropoxyphenyl)-benzokllimidazole o's CI
CI

This compound was prepared by using essentially the same scope of example 1 except by using 2-isopropyloxyphenylboronic acid instead of phenylboronic acid in step 8 to afford the product as a white solid, MS (+) ES: 503 (M+H) .
Example 9 Preparation of 2-(4,6-dichloro-5-(2-isopropoxypheny1)-1H-benzoldlimidazol-2-y1)-2-(4-(ethylsulfonyl)phenyl)ethanol ,0 CI
HO CI

This compound was prepared by essential the same method as of example 4 to afford the product as a white solid, MS (+) ES: 533 (M+H) .
Example 10 Preparation of (4,6-dichloro-5-(2-isopropoxypheny1)-1H-benzo [di imidazol-2-y1)(4-(ethylsulfonyl)phenyl)methanol o o CI
HO N CI
This product was prepared by essentially the same method as of example 2 to afford the 10 product as a white solid, MS (+) ES: 519 (M+H) .
Example 11 Preparation of 2-(4,6-dichloro-5-(2-fluoropheny1)-1H-benzo [di imidazol-2-y1)-2-(4-(ethylsulfonyl)phenyl)ethanol ¨\ -0 CI
os HO CI F

This compound was prepared by essential the same method as of example 4 to afford the product as a white solid, MS (+) ES: 493 (M+H) .
Example 12 Preparation of (4,6-dichloro-5-(2-fluoropheny1)-1H-benzo [di imidazol-2-y1)(4-(ethylsulfonyl)phenyl)methanol ,0 CI
HO N CI

This product was prepared by essentially the same method as of example 2 to afford the product as a white solid, MS (+) ES: 479 (M+H) .
Example 13 Preparation of 4,6-dichloro-2-(4-(ethylsulfonyl)benzy1)-5-(2-(methoxymethoxy)phenyl)-1H-benzoldlimidazole CI

CI

This compound was prepared by using essentially the same scope of example 1 except by using 2-methoxymethoxyphenylboronic acid instead of phenylboronic acid in step 8 to afford the product as a white solid, MS (+) ES: 505 (M+H) .
Example 14 Preparation of 2-(4,6-dichloro-5-(2-methoxymethoxypheny1)-1H-benzo [di imidazol-2-y1)-2-(4-(ethylsulfonyl)phenyl)ethanol ,o o's N CI =
HO /

CI

This compound was prepared by essential the same method as of example 4 to afford the product as a white solid, MS (+) ES: 535 (M+H) .
Example 15 Preparation of (4,6-dichloro-5-(2,5-dichloropheny1)-1H-benzo [di imidazol-2-y1)(4-(ethylsulfonyl)phenyl)methanol ¨\S .0 CI
01' N CI
CI
H= IN 1.1 CI
This product was prepared by essentially the same method as of example 2 to afford the product as a white solid, MS (+) ES: 534(M+H) .
5 Example 16 Preparation of 4,6-dichloro-5-(2-ethoxypheny0-2-(4-(ethylsulfonyl)benzyl)-1H-benzoldlimidazole o N CI
NH CI () This compound was prepared by using essentially the same scope of example 1 except by 10 using 2-ethoxyphenylboronic acid instead of phenylboronic acid in step 8 to afford the product as a white solid, MS (+) ES: 489 (M+H) .
Example 17 Preparation of 2-(4,6-dichloro-5-(2-ethoxypheny1)-1H-benzokllimidazol-2-y1)-2-(4-15 (ethylsulfonyl)phenyl)ethanol ¨\ .0 N CI =
HO /
r:iN CI

This compound was prepared by essential the same method as of example 4 to afford the product as a white solid, MS (+) ES: 519 (M+H) .

Example 18 Preparation of (4,6-dichloro-5-(2-ethoxypheny1)-1H-benzokllimidazol-2-y1)(4-(ethylsulfonyl)phenyl)methanol ,o HO N CI () This product was prepared by essentially the same method as of example 2 to afford the product as a white solid, MS (+) ES: 505 (M+H) .
Example 19 Preparation of 4,6-dichloro-2-(4-(ethylsulfonyl)benzy1)-5-(2-(2-methoxyethoxy)phenyl)-1H-benzoldlimidazole ,o o-s N CI
/
CI C)Or This compound was prepared by using essentially the same scope of example 1 except by using (2-(2-methoxyethoxy)phenyl)boronic acid instead of phenylboronic acid in step 8 to afford the product as a white solid, MS (+) ES: 519 (M+H) .
Example 20 Preparation of 2-(4,6-dichloro-5-(2-(2-methoxyethoxy)pheny1)-1H-benzokllimidazol-2-y1)-2-(4-(ethylsulfonyl)phenyl)ethanol ,0 O'S
* N CI
HO CI
/

N

This compound was prepared by essential the same method as of example 4 to afford the product as a white solid, MS (+) ES: 549 (M+H) .
Example 21 Preparation of (4,6-dichloro-5-(2-(2-methoxyethoxy)pheny1)-1H-benzo [di imidazol-2-y1)(4-(ethylsulfonyl)phenyl)methanol ¨\ -0 s' =
o' HO N CI CjO

This product was prepared by essentially the same method as of example 2 to afford the product as a white solid, MS (+) ES: 535 (M+H) .
Example 22 Preparation of 2-(4,6-dichloro-2-(1-(4-(ethylsulfonyl)pheny1)-2-hydroxyethyl)-benzo [di imidazol-5-yl)benzonitrile ¨\ -0 's o' HO CI CN

This compound was prepared by essential the same method as of example 4 to afford the product as a white solid, MS (+) ES: 500 (M+H) .
Example 23 Preparation of 2-(4,6-dichloro-2-((4-(ethylsulfonyl)phenyl)(hydroxy)methyl)-1H-.. benzo [di imidazol-5-yl)benzonitrile -o o' H= N CICN

This product was prepared by essentially the same method as of example 2 to afford the product as a white solid, MS (+) ES: 486 (M+H) .
Example 24 .. Preparation of 4,6-dichloro-2-(4-(ethylsulfonyl)benzy1)-5-(thiophen-3-y1)-benzoldlimidazole ¨\ 0 CI
N
CI

This compound was prepared by using essentially the same scope of example 1 except by using 3-thiophenylboronic acid instead of phenylboronic acid in step 8 to afford the product as a white solid, MS (+) ES: 451 (M+H) .
Example 25 Preparation of 2-(4,6-dichloro-5-(thiophen-3-y1)-1H-benzokllimidazol-2-y1)-2-(4-(ethylsulfonyl)phenyl)ethanol ,0 10'S
* N
/
CI ....-HO *
CI

This compound was prepared by essential the same method as of example 4 to afford the product as a white solid, MS (+) ES: 481 (M+H) .
Example 26 Preparation of (4,6-dichloro-5-(thiophen-3-y1)-1H-benzokllimidazol-2-y1)(4-(ethylsulfonyl)phenyl)methanol ¨\ S' .0 0-p, HO IN * CI

This product was prepared by essentially the same method as of example 2 to afford the product as a white solid, MS (+) ES: 467 (M+H) .
Example 27 Preparation of 2-(4,6-dichloro-2-(4-(ethylsulfonyl)benzy1)-1H-benzokllimidazol-5-y1)-N,N-dimethylaniline S' * IN 01 01 CI /

This compound was prepared by using essentially the same scope of example 1 except by using (2-(dimethylamino)phenyl)boronic acid instead of phenylboronic acid in step 8 to afford the product as a white solid, MS (+) ES: 488 (M+H) .
Example 28 Preparation of 4,6-dichloro-5-(2-(difluoromethoxy)pheny1)-2-(4-(ethylsulfonyflbenzy1)-1H-benzoldlimidazole ,0 0' -S' /

This compound was prepared by using essentially the same scope of example 1 except by using 2-difluoromethoxyphenylboronic acid pinacol ester instead of phenylboronic acid in step 8 to afford the product as a white solid, MS (+) ES: 511 (M+H) .

Example 29 Preparation of 2-(4,6-dichloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo ldlimidazol-2-y1)-2-(4-(ethylsulfonyl)phenyl)ethanol ¨so O'"

.. This compound was prepared by essential the same method as of example 4 to afford the product as a white solid, MS (+) ES: 541 (M+H) .
Example 30 Preparation of (4,6-dichloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo [di imidazol-2-y1)(4-(ethylsulfonyl)phenyl)methanol ,0 Os N CI =
HO N a OCH F2 This product was prepared by essentially the same method as of example 2 to afford the product as a white solid, MS (+) ES: 527 (M+H) .
15 Example 31 Preparation of 4,6-dichloro-2-(4-(ethylsulfonyl)benzy1)-5-(2-(2,2,2-trifluoroethoxy)pheny1)-1H-benzoldlimidazole S, *13 N CI
/

This compound was prepared by using essentially the same scope of example 1 except by 20 using 4,4,5,5-tetramethy1-2-(2-(2,2,2-trifluoroethoxy)pheny1)-1,3,2-dioxaborolane instead of phenylboronic acid in step 8 to afford the product as a white solid, MS (+) ES: 543 (M+H) .

Example 32 Preparation of 2-(4,6-dichloro-5-(2-(2,2,2-trifluoroethoxy)pheny0-1H-benzo [di imidazol-2-y1)-2-(4-(ethylsulfonyl)phenyl)ethanol ¨\ /0 0' ,S' I I.
*HO a 0./CF 3 This compound was prepared by essential the same method as of example 4 to afford the product as a white solid, MS (+) ES: 573 (M+H) .
Example 33 Preparation of (4,6-dichloro-5-(2-(2,2,2-trifluoroethoxy)pheny0-1H-benzoldlimidazol-2-y1)(4-(ethylsulfonyl)phenyl)methanol ,o os II

This product was prepared by essentially the same method as of example 2 to afford the product as a white solid, MS (+) ES: 559 (M+H) .
Example 34 Preparation of 4,6-dichloro-2-(4-(ethylsulfonyflbenzy1)-5-(2-(3,3,3-trifluoropropyflpheny1)-1H-benzoldlimidazole ¨\
0' CI

This compound was prepared by using essentially the same scope of example 1 except by using 4,4,5,5-tetramethy1-2-(2-(3,3,3-trifluoropropyl)pheny1)-1,3,2-dioxaborolane instead of phenylboronic acid in step 8 to afford the product as a white solid, MS (+) ES: 541 (M+H) Example 35 Preparation of (4,6-dichloro-5-(2-(3,3,3-trifluoropropyl)pheny1)-1H-benzokllimidazol-2-y1)(4-(ethylsulfonyl)phenyl)methanol .0 O'S
CI

This product was prepared by essentially the same method as of example 2 to afford the 10 product as a white solid, MS (+) ES: 557 (M+H) .
Example 36 Preparation of 4,6-dichloro-2-(4-(ethylsulfonyl)benzy1)-5-(2-isopropylphenyl)-benzoldlimidazole ¨\
CI
CI

This compound was prepared by using essentially the same scope of example 1 except by using 2-isopropylphenylboronic acid instead of phenylboronic acid in step 8 to afford the product as a white solid, MS (+) ES: 487 (M+H) .
20 Example 37 Preparation of 2-(4,6-dichloro-5-(2-isopropylpheny1)-1H-benzokllimidazol-2-y1)-2-(4-(ethylsulfonyl)phenyl)ethanol ¨\ -0 CC's =N CI
/
HO CI

This compound was prepared by essential the same method as of example 4 to afford the product as a white solid, MS (+) ES: 517 (M+H) .
Example 38 Preparation of (E,Z)-(4,6-dichloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo [di imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanone wdme ,o o-s ci HO¨N
ci OCHF2 N

¨\ 0 ¨\ 0 EZ
Hydroxyamine N I 41 /=

CI OC HF2 Pyriding, 70 C, 2h HO¨N N CI
OC
The mixture of (4,6-dichloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo [di imidazol-2-yl)(4-(ethylsulfonyl)phenyl)methanone (52 mg, 0.1 mmol) and hydroxylamine hydrochloride (14 mg, 0.2 mmol) in anhydrous pyridine (1 ml) was heated to 70 C for 2 h.
After cooling, the solvent was evaporated under reduced pressure to dryness. The product was purified by flash chromatography with hexane/ethyl acetate to afford the product as a white solid (42 mg, 78%), MS (+) ES: 540 (M+H) .
Example 39 Preparation of (4,6-dichloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo [di imidazol-2-y1)(4-(ethylsulfonyl)phenyl)methanamine s-c) CI

-\ 0 -C) O'S
O'S

CI

EZ
The mixture of (E,Z)-(4,6-dichloro-5-(2-(difluoromethoxy)pheny1)-1H-benzoldlimidazol-2-y1)(4-(ethylsulfonyl)phenyemethanone oxime (42 mg, 0.078 mmol) was dissolved in anhydrous THF (2 ml). To this solution was added borane 1M THF
solution (4 ml) and the mixture was stirred at room temperature overnight. The volatile solvents were evaporated under reduced pressure and the residue was directly purified by Prep HPLC with elution system C to afford a white solid (18 mg, 45%), MS (+) ES: 526 (M+H) .
Example 40 Preparation of N4(4,6-dichloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo [di imidazol-2-y1)(4-(ethylsulfonyl)phenyl)methyllacetamide o's CI

o CrS 0' N I
[40 O CI
H2N N CH F2 )-NH N OCH F2 15 Acetyl chloride solution (in DCM) (leq) was added to a cooled solution (ice-water bath) of (4,6-dichloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo [di imidazol-2-y1)(4-(ethylsulfonyl)phenyl)methanamine (example 39) (4 mg, 0.0076 mmol) and triethyl amine (1 eq) in dichloromethane (0.5 ml). The mixture was stirred for 30 mm before the dichloromethane was evaporated. The residure was directly separated by Prep HPLC with 20 elution system C to afford a white solid (2.6 mg, 42%), MS (+) ES: 568 (M+H) .

Example 41 Preparation of N4(4,6-dichloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo [di imidazol-2-y1)(4-(ethylsulfonyl)phenyl)methyl)-2-methoxyacetamide ,o ,s-o-CI

a OCH F2 \¨NH
JJJ

¨\ 0 CfS
CI
CI

Similar method was applied as of example 40 to give the product as a white solid, MS (+) ES:
598 (M+H) .
Example 42 Preparation of N4(4,6-dichloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo [di imidazol-2-y1)(4-(ethylsulfonyl)phenyl)methyl)-3,5-dimethylisoxazole-4-carboxamide ,o CI

NH N CI
0)77.

¨so 0*S
CI CI
ci OCHF2 /1\I
=

Similar method was applied as of example 40 to give the product as a white solid, MS (+) ES:
649 (M+H) .

Example 43 Preparation of (4,6-dichloro-5-(2-(trifluoromethoxy)pheny0-1H-benzokllimidazol-2-y1)(4-(ethylsulfonyl)phenyl)methanamine o's CI

Similar method was applied as of example 39 to give the product as a white solid, MS (+) ES:
544 (M+H) .
Example 44 Preparation of N4(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzokllimidazol-2-yl)(4-(ethylsulfonyl)phenyl)methyllacetamide ¨\
¨NH
o's CI

ci OCF3 ¨so (:)S
CI
CI

)¨NH CI OCF3 Similar method was applied as of example 40 to give the product as a white solid, MS (+) ES:
586 (M+H) .
Example 45 Preparation of 4,6-dichloro-2-(4-(methylsulfonyl)benzy1)-5-(2-(trifluoromethyl)pheny1)-1H-benzoldlimidazole \ ,o o's a c F3 This compound was prepared by using essentially the same scope of example 1 to afford the product as a white solid, MS (+) ES: 499 (M+H) .
Example 46 Preparation of 2-(4,6-dichloro-5-(2-(trifluoromethyl)pheny1)-1H-benzoldlimidazol-2-y1)-2-(4-(methylsulfonyl)phenyl)ethanol \
cpr's N CI =
CF
HO N = CI 3 This compound was prepared by essential the same method as of example 4 to afford the product as a white solid, MS (+) ES: 529 (M+H) .
Example 47 Preparation of 4,6-dichloro-5-(2-(difluoromethoxy)pheny1)-2-(4-(methylsulfonyl)benzyl)-1H-benzoldlimidazole \
* N CI
/
ciOC HF2 This compound was prepared by using essentially the same scope of example 28 to afford the product as a white solid, MS (+) ES: 497 (M+H) .
Example 48 Preparation of 2-(4,6-dichloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo ldlimidazol-2-y1)-2-(4-(methylsulfonyl)phenyl)ethanol \ 0 This compound was prepared by essential the same method as of example 29 to afford the product as a white solid, MS (+) ES: 527 (M+H) .
Example 49 Preparation of (4,6-dichloro-5-(2-(difluoromethoxy)pheny1)-1H-benzokllimidazol-2-y1)(4-(methylsulfonyl)phenyl)methanol \
's HO /N * CI

This product was prepared by essentially the same method as of example 30 to afford the product as a white solid, MS (+) ES: 513 (M+H) .
Example 50 Preparation of 4,6-dichloro-2-(4-(propylsulfonyflbenzy1)-5-(2-(trifluoromethoxy)pheny1)-1H-benzoldlimidazole CI

15 This compound was prepared by using essentially the same scope of example 1 to afford the product as a white solid, MS (+) ES: 543 (M+H) .
Example 51 Preparation of 2-(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzokllimidazol-2-y1)-2-20 (4-(propylsulfonyl)phenyl)ethanol ,o s--= I
HO ci OC F3 This compound was prepared by essential the same method as of example 6 to afford the product as a white solid, MS (+) ES: 573 (M+H) .
Example 52 Preparation of (4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo [di imidazol-2-y1)(4-(propylsulfonyl)phenyl)methanol \--\
s.

This product was prepared by essentially the same method as of example 7 to afford the product as a white solid, MS (+) ES: 559 (M+H) .
Example 53 Preparation of 4,6-dichloro-2-(4-42-methoxyethypsulfonyflbenzy1)-5-(2-(trifluoromethoxy)phenyl)-1H-benzo [di imidazole ¨o -o This compound was prepared by using essentially the same scope of example 1 to afford the product as a white solid, MS (+) ES: 559 (M+H) .
Example 54 Preparation of 2-(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo [di imidazol-2-y1)-2-(4-((2-methoxyethyl)sulfonyl)phenyl)ethanol ¨o -o -o ci HO
so This compound was prepared by essential the same method as of example 6 to afford the product as a white solid, MS (+) ES: 589 (M+H) .
Example 55 Preparation of (4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo [di imidazol-2-y1)(4-((2-methoxyethyl)sulfonyl)phenyl)methanol HO
ci OC F3 N
This product was prepared by essentially the same method as of example 7 to afford the product as a white solid, MS (+) ES: 575 (M+H) .
Example 56 Preparation of 4,6-dichloro-2-(4-(methylsulfonyl)benzy1)-5-(2-(trifluoromethoxy)pheny1)-1H-benzoldlimidazole \
(:)*s * N CI
/
ci OC F3 This compound was prepared by using essentially the same scope of example 1 to afford the product as a white solid, MS (+) ES: 515 (M+H) .
Example 57 Preparation of 2-(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo [di imidazol-2-y1)-2-(4-(methylsulfonyl)phenyl)ethanol \ s,o -HO ci OC F3 This compound was prepared by essential the same method as of example 6 to afford the product as a white solid, MS (+) ES: 545 (M+H) .
Example 58 Preparation of (4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo [di imidazol-2-y1)(4-(methylsulfonyl)phenyl)methanol \ ,o HO
ci OCF3 N

This product was prepared by essentially the same method as of example 7 to afford the product as a white solid, MS (+) ES: 531 (M+H) .
Example 59 Preparation of 4,6-dichloro-2-(4-42,2,2-trifluoroethypsulfonyflbenzy1)-5-(2-(trifluoromethoxy)phenyl)-1H-benzo [di imidazole ,o F
CC'S
N CI
/

This compound was prepared by using essentially the same scope of example 1 to afford the product as a white solid, MS (+) ES: 583 (M+H) .
Example 60 Preparation of 2-(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo [di imidazol-2-y1)-2-(4-((2,2,2-trifluoroethyl)sulfonyl)phenyl)ethanol F, F¨)¨\
F
0 'S
= N C I =

This compound was prepared by essential the same method as of example 6 to afford the product as a white solid, MS (+) ES: 613 (M+H) .
Example 61 Preparation of 4,6-dichloro-2-(4-((2-fluoroethyl)sulfonyflbenzy1)-5-(2-(trifluoromethoxy)pheny1)-1H-benzo [di imidazole S.*
01"
N CI

This compound was prepared by using essentially the same scope of example 1 to afford the product as a white solid, MS (+) ES: 547 (M+H) .
Example 62 Preparation of 2-(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo [di imidazol-2-y1)-2-(4-((2-fluoroethyl)sulfonyl)phenyl)ethanol -o a HO *a OCF3 This compound was prepared by essential the same method as of example 4 to afford the product as a white solid, MS (+) ES: 577 (M+H) .
Example 63 Preparation of 4,6-dichloro-2-(4-((2-fluoroethyl)sulfonyflbenzy1)-5-(2-(trifluoromethyl)pheny1)-1H-benzo [di imidazole * N CI
/

This compound was prepared by using essentially the same scope of example 1 to afford the product as a white solid, MS (+) ES: 531 (M+H) .
Example 64 Preparation of 2-(4,6-dichloro-5-(2-(trifluoromethyl)pheny1)-1H-benzoldlimidazol-2-y0-2-(4-((2-fluoroethyl)sulfonyl)phenyflethanol µ--\
o*s' N CI
HO /

This compound was prepared by essential the same method as of example 4 to afford the product as a white solid, MS (+) ES: 561 (M+H) .
Example 65 Preparation of 4,6-dichloro-5-(2-(trifluoromethyflpheny1)-2-(4-((trifluoromethyl)sulfonyl)benzy1)-1H-benzo [di imidazole F-Ns,*0 C I la /1\1 This compound was prepared by using essentially the same scope of example 1 to afford the product as a white solid, MS (+) ES: 553 (M+H) .

Example 66 Preparation of 4,6-dichloro-2-(4-((cyclopropylmethyl)sulfonyflbenzy1)-5-(2-(trifluoromethoxy)pheny1)-1H-benzo [di imidazole I>--\
o's * N C I
/

.. This compound was prepared by using essentially the same scope of example 1 to afford the product as a white solid, MS (+) ES: 555 (M+H) .
Example 67 Preparation of 2-(4-((cyclopropylmethypsulfonyflpheny1)-2-(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo [di imidazol-2-yDethanol ,0 o's N CI =
HO /
OC
a This compound was prepared by essential the same method as of example 4 to afford the product as a white solid, MS (+) ES: 585 (M+H) .
Example 68 Preparation of (4-((cyclopropylmethyl)sulfonyl)phenyl)(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo [di imidazol-2-yl)methanol a HO N a OCF3 This product was prepared by essentially the same method as of example 2 to afford the .. product as a white solid, MS (+) ES: 571 (M+H) .

Example 69 Preparation of 4,6-dichloro-2-(4-((cyclopropylmethyl)sulfonyflbenzy1)-5-(2-(trifluoromethyl)pheny1)-1H-benzo [di imidazole >\0.
a's a This compound was prepared by using essentially the same scope of example 1 to afford the product as a white solid, MS (+) ES: 539 (M+H) .
Example 70 Preparation of 2-(4-((cyclopropylmethypsulfonyflpheny1)-2-(4,6-dichloro-5-(2-(trifluoromethyl)pheny1)-1H-benzo [di imidazol-2-yDethanol o's a This compound was prepared by essential the same method as of example 4 to afford the product as a white solid, MS (+) ES: 569 (M+H) .
15 Example 71 Preparation of (4-((cyclopropylmethyl)sulfonyl)phenyl)(4,6-dichloro-5-(2-(trifluoromethyl)pheny1)-1H-benzo [di imidazol-2-yl)methanol o's a HO N * CI

This product was prepared by essentially the same method as of example 2 to afford the 20 product as a white solid, MS (+) ES: 555 (M+H) .

Example 72 Preparation of 4,6-dichloro-2-(4-((cyclopropylmethyl)sulfonyl)benzy1)-5-(2-(difluoromethoxy)pheny0-1H-benzo [di imidazole * N CI

This compound was prepared by using essentially the same scope of example 1 to afford the product as a white solid, MS (+) ES: 537 (M+H) .
Example 73 Preparation of 2-(4-((cyclopropylmethypsulfonyl)phenyl)-2-(4,6-dichloro-5-(2-(difluoromethoxy)pheny0-1H-benzo [di imidazol-2-yDethanol 1>¨\
o's a =
IN

This compound was prepared by essential the same method as of example 4 to afford the product as a white solid, MS (+) ES: 567 (M+H) .
Example 74 Preparation of 2-(4-((cyclopropylmethypsulfonyl)phenyl)-2-(4,6-dichloro-5-(2-fluoropheny1)-1H-benzo [di imidazol-2-yDethanol ,o o' HO CI

This compound was prepared by essential the same method as of example 4 to afford the product as a white solid, MS (+) ES: 519 (M+H) .

Example 75 Preparation of (4-((cyclopropylmethyl)sulfonyl)phenyl)(4,6-dichloro-5-(2-fluoropheny1)-1H-benzokllimidazol-2-y1)methanol 1>----\s'o (:).?

H
5 This product was prepared by essentially the same method as of example 2 to afford the product as a white solid, MS (+) ES: 505 (M+H) .
Example 76 Preparation of 4,6-dichloro-2-(4-(ethylsulfony1)-2-fluorobenzy1)-5-(2-10 (trifluoromethoxy)pheny1)-1H-benzokllimidazole F, X-F

11.0 S' HN
N CI
F

NaNO2/HCI
02N F 0 H2SO4 02N F 0 Pd/C, H2 H2N F 0 S' OH Me0H 0 Et0H 0 KS0---''.

HS F 0 -------,1 MCPBA ..,0 F _ S 0 F 0 ____________ 0 _________________________ ...
Ch2Cl2 (:) Cs2CO3/DMF 0 0 H2N ill CI
0 H2N Br 0 11.0 11,0 1. NaOH --...õ-S F 0 CI =-......,õS' U2N 0 Br CI HOAc _,...
_____________ . reflux 2. HCI OH HATU, DIEA, DMF N
H
F CI
F
CI VF

11.0 =-=.õ,._,..S
HN . Br Pd2(dba)3, Rt-Eu3)PHIEF4 ......,,,,S' a- HN
N CI aq Na2CO3, dioxane N CI
F
F

Step 1. Preparation of methyl 2-(2-fluoro-4-nitrophenyl)acetate OH meoH
2-(2-fluoro-4-nitrophenyl)acetic acid (4.0 g, 0.02 mol) in methanol (20 ml) was added concentrated sulfuric acid (1 ml). The solution was heated to reflux overnight. After cooling, the mixture was concentrated to a small amount and partitioned between ether (30 ml) and water. The ether phase was separated and washed with saturated sodium bicarbonate solution (30 m1). The organic phase was then separated again and washed with water, dried over MgSO4. The solid was filtered off and evaporation of the solvent to give the product pure enough for the next step (3.8 g, 88%), MS (+) ES: 214 (M+H) .
Step 2. Preparation of methyl 2-(4-amino-2-fluorophenyl)acetate 0 Me0H 0 To a 50 ml round bottom flask, were added methyl 2-(2-fluoro-4-nitrophenyl)acetate (3.8 g, 0.018 mol) and ethyl acetate (30 ml). To the same flask, 10 percent palladium on activated carbon (0.5 g) was added. The reaction mixture was stirred under hydrogen gas (using bladder) atmosphere for 5 h. The reaction mixture was filtered through a pad of celite.
The filtrate was evaporated under reduced pressure to get the title compound (2.8 g, 86%), MS (+) ES: 184 (M+H) .
Step 3. Preparation of 2-(2-fluoro-4-mercaptophenyl)acetic acid NaNO2/HCI
3,, HS F 0 O OH

A solution of sodium nitrite (1.06 g, 0.015 mol) in 16 ml of water was added drop wise at 0 C, to a stirred suspension of methyl 2-(4-amino-2-fluorophenyl)acetate (2.8 g, 0.015 mol) in 50 ml of water and 3.8 ml of concentrated hydrochloric acid.
After the addition was complete, the reaction mixture was stirred at the same temperature for a further 60 minutes. This cold diazonium salt solution was then added dropwise at room temperature to a mixture of potassium 0-ethyl carbonodithioate (2.8 g), 50 ml of water and 16 ml of a 2 M
sodium carbonate solution, and was heated to 45 C until gas evolution stopped.
The mixture was cooled to room temperature, and the pH was adjusted to 1 with concentrated hydrochloric acid. The oiled xanthogenate ester was extracted with ether.
Solvent was evaporated to give a dark red liquid 2-(4-(ethoxycarbonothioyl)tliio)-2-fluorophenyllacetic acid methyl ester (3.5 g), MS (+) ES: 288 (M+H) .
The above oily product was dissolved in ethanol (10 ml), a solution of KOH
(1.8g) in water (10 ml) was added and the mixture heated to reflux overnight. The mixture was concentrated to a small amount and acidified with concentrated HC1. The product was extracted with ethyl acetate (10 ml X 3). The combined organic phase was dried over MgSO4 , the solid was filtered off. Evaporation of the solvent to afford the crude product (2.5 g, 89%), MS (+) ES: 187 (M+H) .
Step 4. Preparation of ethyl 2-(4-(ethylthio)-2-fluorophenyl)acetate HS F=
F
OH Cs20 03/ DM F 0 2-(2-fluoro-4-mercaptophenyl)acetic acid (2.5 g, 0.013 mol) was dissolved in DMF
(25 ml), followed by the addition of cesium carbonate (13.0 g, 0.039 mol). The mixture was stirred for 10min before Iodoethane (6g, 0.039 mol) was added and the mixture was stirred at room temp overnight. The reaction mixture was partitioned between ethyl acetate (20 ml) and water (30 ml). The organic phase was separated and dried over MgSO4. The solid was filtered off and the solvent was evaporated to dryness. This product was purified by flash chromatography with hexane/ethyl acetate to afford an oil (2.8 g, 86%), MS (+) ES: 243 (M+H) .
Step 5. Preparation of ethyl 2-(4-(ethylsulfony1)-2-fluorophenyl)acetate 0, _____________________________________ cH2ci2 Ethyl 2-(4-(ethylthio)-2-fluorophenyl)acetate (2.8 g, 0.012 mol) was dissolved in DCM (50 m1). The solution was cooled to 0 C with an ice bath. MCPBA (6.0 g) was added in portions. The reaction mixture was stirred at room temperature overnight, and then filtered to remove the solid. The filtrate was washed with sat. sodium carbonate solution (30 ml x 2), water (30 ml), brine (30 ml), dried over magnesium sulfate, and concentrated.
The residue was purified by column chromatography with hexane/ethyl acetate to afford the target compound ethyl 2-(4-(ethylsulfony1)-2-fluorophenyl)acetate (2.0 g, 64%), MS
(+) ES: 275 (M+H) .

Step 6. Preparation of 2-(4-(ethylsulfony1)-2-fluorophenyeacetic acid 0 1 . NaOH 0 11,0 F F

140) 2. H CI OH
To a solution of ethyl 2-(4-(ethylsulfony1)-2-fluorophenyeacetate (2.0 g, 7.3 mmol) in ethanol (30 ml) was added a solution of NaOH (1.0 g) in water (10 m1). The reaction mixture was stirred at room temperature overnight. Ethanol was removed under reduced pressure, and 20 mL of water was added. The aqueous phase was acidified to pH = 1 with 6 M
HC1, and then extracted with ethyl acetate (50 ml x 3). The combined organic phases were washed with brine (50 ml), dried over magnesium sulfate, and concentrated to afford an oil which solidified upon standing (1.6 g, 90%), MS(+) ES: 247 (M+H) .
Step 7. Preparation of N-(6-amino-3-bromo-2,4-dichloropheny0-2-(4-(ethylsulfony0-2-fluorophenyeacetamide H2N Br i(:) CI CI

Br OH EDCI, HOBt/DMF
CI
1-Ethyl-(3-(3-dimethylamino)propy1)-carbodiimide hydrochloride (1.0 g, 5 mmol) and benzotriazol-l-ol (0.7 g, 5 mmol) were added into a cooled solution (ice water bath) of 4-bromo-3,5-dichlorobenzene-1,2-diamine (1.28 g, 5 mmol) and 2-(4-(ethylsulfony1)-2-fluorophenyeacetic acid (example 93, step 6, 1.23 g, 5 mmol) in DMF (10 ml) portion wise.
After the addition was completed, the mixture was stirred for 60 mm and was allowed to warm-up to room temp, stirred overnight. The mixture was partitioned between water (50 ml) and ethyl acetate (50 m1). The organic phase was separated and dried over MgSO4, filtered. The solvent was evaporated under reduced pressure to leave a off-white solid which was purified by flash chromatography with hexane/ethyl acetate to afford the product as a solid (1.7 g, 70%), MS (+) ES: 484 (M+H) .
Step 8. Preparation of 5-bromo-4,6-dichloro-2-(4-(ethylsulfony1)-2-fluorobenzy1)-1H-benzoldlimidazole oi H2N =Br CI HOAc HN 411 Br reflux oi CI

N-(6-amino-3 -bro mo -2,4 -dichloropheny1)-2- (4 -(ethylsulfo ny1)-2-fluorophenyl) acetamide (step 7) (1.7 g, 3.5 mmol) was mixed with acetic acid (10 ml) and the mixture was heated to 100 C for 4 hours, cooled. The solvent was evaporated under reduce pressure and the residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate, dried over MgSO4. This product was purified by flash chromatography with hexane/ethyl acetate to afford the product as a white solid (1.2 g, 73%), MS
(+) ES: 466 (M+H) .
Step 9. Preparation of 4,6-dichloro-2-(4-(ethylsulfony1)-2-fluorobenzy1)-5-(2-(trifluoromethoxy)pheny1)- 1H-benzo [di imid azole CI
=,o F
HN r Pd2(dba)3, [(t-B u3)PHIBF4, 0 CI 0 ,11,0 aq. Na2CO3, dioxane HN le N CI
N CI
A mixture of 5-bromo-4,6-dichloro-2 -(4-(ethyl su lfony1)-2-flu orobenzy1)- 1H-benzoldlimidazole (step 8) (47 mg, 0.1 mmol), 2-trifluoromethoxyphenylboronic acid (62 mg, 0.3 mmol), tris-(dibenzylideneacetone)dipalladium(0) (6 mg), tri(tert-butyl)phosphonium tetrafluoroboronate (6 mg) and sodium carbonate (2M solution) in 1,4-dioxane (0.6 ml) was .. degassed and heated to 100 C under Microwave irradiation for lh. The volatile solvents were removed under reduced pressure. The residue was directly loaded onto a ISCO solid cartridge and flashed with hexane/ethyl acetate to afford a white solid product (38 mg, 70%
yield), MS (+) ES: 547 (M+H) .
Example 77 Preparation of 2-(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzokllimidazol-2-y1)-2-(4-(ethylsulfony1)-2-fluorophenyl)ethanol Fx_ 11.0 =S' HN
OHN CI

This compound was prepared by essential the same method as of example 4 to afford the product as a white solid, MS (+) ES: 577 (M+H) .

Example 78 Preparation of (4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo [di imidazol-2-y1)(4-(ethylsulfony1)-2-fluorophenyl)methanol )7F

1,1-30 HN 41, N CI
F OH

This compound was prepared by essential the same method as of example 2 to afford the product as a white solid, MS (+) ES: 563 (M+H) .
Example 79 Preparation of (4,6-dichloro-5-(2-(trifluoromethyl)pheny1)-1H-benzo [di imidazol-2-y1)(4-(ethylsulfony1)-2-fluorophenyl)methanol ci CF3 =/ HN
N CI
F OH

This compound was prepared by essential the similar method as of example 78 to afford the product as a white solid, MS (+) ES: 547 (M+H) .
Example 80 Preparation of 4,6-dichloro-2-(4-((cyclopropylmethyl)sulfony1)-2-fluorobenzy1)-5-(2-(trifluoromethoxy)pheny1)-1H-benzo [di imidazole F F
Y-F

HN
N CI
This compound was prepared by essential the similar method as of example 76 to afford the 20 product as a white solid, MS (+) ES: 573 (M+H) .

Example 81 Preparation of 2-(4-((cyclopropylmethyl)sulfony1)-2-fluoropheny1)-2-(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo [di imidazol-2-yDethanol F F
Y-F

HN
N CI
OH

This compound was prepared by essential the similar method as of example 77 to afford the product as a white solid, MS (+) ES: 603 (M+H) .
Example 82 Preparation of (4-((cyclopropylmethyl)sulfony1)-2-fluorophenyl)(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo [di imidazol-2-yl)methanol F,F
/-F

A6'4 HN
N CI
F OH

This compound was prepared by essential the similar method as of example 78 to afford the product as a white solid, MS (+) ES: 589 (M+H) .
Example 83 Preparation of 4,6-dichloro-5-(2-(difluoromethoxy)pheny1)-2-(4-(ethylsulfony1)-fluorobenzy1)-1H-benzo [di imidazole )-F

91, 0 HN
N CI

This compound was prepared by essential the same method as of example 76 by using 2-difluorophenylboronic acid instead of 2-trifluoromethoxyphenylboronic acid in step 9 to afford the product as a white solid, MS (+) ES: 529 (M+H) .

Example 84 Preparation of 2-(4,6-dichloro-5-(2-(difluoromethoxy)pheny0-1H-benzoldlimidazol-2-y0-2-(4-(ethylsulfony0-2-fluorophenyl)ethanol CI
(t? 0 CI
OH

This compound was prepared by essential the similar method as of example 77 to afford the product as a white solid, MS (+) ES: 559 (M+H) .
Example 85 Preparation of (4,6-dichloro-5-(2-(difluoromethoxy)pheny0-1H-benzo [di imidazol-2-y1)(4-(ethylsulfony0-2-fluorophenyl)methanol F, )-F

Vp411 HIV le N CI
F OH
This compound was prepared by essential the similar method as of example 78 to afford the product as a white solid, MS (+) ES: 545 (M+H) .
15 Example 86 Preparation of 4,6-dichloro-2-(2-chloro-4-(ethylsulfonyl)benzy1)-5-(2-(trifluoromethoxy)pheny1)-1H-benzo [di imidazole F F
Y-F

91, 0 HN
'N CI
CI

This compound was prepared by essential the similar method as of example 76 to afford the 20 product as a white solid, MS (+) ES: 563 (M+H) .

Example 87 Preparation of 2-(2-chloro-4-(ethylsulfonyl)pheny1)-2-(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo ldlimidazol-2-yl)ethanol F F
Y-F

=/µ.34 HN
N CI
CI
OH

This compound was prepared by essential the similar method as of example 77 to afford the product as a white solid, MS (+) ES: 593 (M+H) .
Example 88 Preparation of (2-chloro-4-(ethylsulfonyl)phenyl)(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo [di imidazol-2-yl)methanol F F
Y-F

91, 0 HN
N CI
CI OH

This compound was prepared by essential the similar method as of example 78 to afford the product as a white solid, MS (+) ES: 579 (M+H) .
Example 89 Preparation of 4,6-dichloro-2-(2-chloro-4-(ethylsulfonyl)benzy1)-5-(2-(difluoromethoxy)pheny1)-1H-benzo [di imidazole )-F

HN
N CI
CI

This compound was prepared by essential the similar method as of example 76 to afford the product as a white solid, MS (+) ES: 545 (M+H) .

Example 90 Preparation of 4,6-dichloro-2-(2-chloro-4-((cyclopropylmethyl)sulfonyl)benzy1)-5-(2-(trifluoromethoxy)pheny1)-1H-benzo [di imidazole F F
Y-F

N CI
CI
5 This compound was prepared by essential the similar method as of example 76 to afford the product as a white solid, MS (+) ES: 589 (M+H) .
Example 91 Preparation of 2-(2-chloro-4-((cyclopropylmethyl)sulfonyepheny1)-2-(4,6-dichloro-5-(2-10 (trifluoromethoxy)pheny1)-1H-benzo [di imidazol-2-yDethanol F F
Y-F

AN;0 = HN
N CI
CI
OH

This compound was prepared by essential the similar method as of example 77 to afford the product as a white solid, MS (+) ES: 619 (M+H) .
15 Example 92 Preparation of (2-chloro-4-((cyclopropylmethyl)sulfonyflphenyl)(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo [di imidazol-2-yl)methanol F F
Y-F

N CI
CI OH

This compound was prepared by essential the similar method as of example 78 to afford the 20 product as a white solid, MS (+) ES: 605 (M+H) .

Example 93 Preparation of 4,6-dichloro-5-(2-chloropheny1)-2-(4-((cyclopropylmethyl)sulfonyl)benzyl)-1H-benzoldlimidazole '60140 HN
N ci This compound was prepared by essential the similar method as of example 76 to afford the product as a white solid, MS (+) ES: 505 (M+H) .
Example 94 Preparation of (4-((cyclopropylmethyl)sulfonyl)phenyl)(4,6-dichloro-5-(2-chloropheny1)-1H-benzo [di imidazol-2-yl)methanol ANJ*4 HN
N CI
OH

This compound was prepared by essential the similar method as of example 78 to afford the product as a white solid, MS (+) ES: 521 (M+H) .
Example 95 Preparation of 2-(4,6-dichloro-2-(4-((cyclopropylmethyl)sulfonyebenzy1)-1H-benzo [di imidazol-5-yl)benzonitrile HN CI NC

A6'4 N CI
20 This compound was prepared by essential the similar method as of example 76 to afford the product as a white solid, MS (+) ES: 496 (M+H) .

Example 96 Preparation of 2-(4,6-dichloro-2-(1-(4-((cyclopropylmethyl)sulfonyl)pheny1)-2-hydroxyethyl)-1H-benzo [di imidazol-5-yflbenzonitrile CI NC

HN
N CI
OH

This compound was prepared by essential the similar method as of example 77 to afford the product as a white solid, MS (+) ES: 526 (M+H) .
Example 97 Preparation of 2-(4,6-dichloro-2-((4-((cyclopropylmethyl)sulfonyl)phenyl)(hydroxy)methyl)-1H-benzo [di imidazol-5-yflbenzonitrile CI NC
'60F00 HN
N CI
OH

This compound was prepared by essential the similar method as of example 78 to afford the product as a white solid, MS (+) ES: 512 (M+H) .
Example 98 Preparation of 4,6-dichloro-2-(4-((cyclopropylmethyl)sulfony1)-2-fluorobenzy1)-5-(2-(difluoromethoxy)pheny1)-1H-benzo [di imidazole F, )-F

AN; 40 HN
N CI

This compound was prepared by essential the similar method as of example 76 to afford the product as a white solid, MS (+) ES: 555 (M+H) .

Example 99 Preparation of 2-(4-((cyclopropylmethyl)sulfony1)-2-fluoropheny1)-2-(4,6-dichloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo [di imidazol-2-yDethanol Fµ

'Ag140 HN
N CI
OH

This compound was prepared by essential the similar method as of example 77 to afford the product as a white solid, MS (+) ES: 585 (M+H) .
Example 100 Preparation of (4-((cyclopropylmethyl)sulfony1)-2-fluorophenyl)(4,6-dichloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo [di imidazol-2-yl)methanol F, )-F

Ag140 HN
N CI
F OH

This compound was prepared by essential the similar method as of example 78 to afford the product as a white solid, MS (+) ES: 571 (M+H) .
Example 101 Preparation of 4,6-dichloro-2-(2-chloro-4-(methylsulfonyflbenzy1)-5-(2-(trifluoromethoxy)pheny1)-1H-benzo [di imidazole F,F
X-F

/g4 HN
N CI
CI

This compound was prepared by essential the similar method as of example 76 to afford the product as a white solid, MS (+) ES: 549 (M+H) .

Example 102 Preparation of 2-(2-chloro-4-(methylsulfonyl)pheny1)-2-(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo [di imidazol-2-yDethanol /g000 N CI
CI
OH

This compound was prepared by essential the similar method as of example 77 to afford the product as a white solid, MS (+) ES: 579 (M+H) .
Example 103 Preparation of (2-chloro-4-(methylsulfonyl)phenyl)(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo [di imidazol-2-yl)methanol F F
Y-F

11..0 HN
N CI
CI OH

This compound was prepared by essential the similar method as of example 78 to afford the product as a white solid, MS (+) ES: 565 (M+H) .
Example 104 Preparation of 4,6-dichloro-2-(4-((isopropylsulfonyl)benzy1)-5-(2-(trifluoromethoxy)phenyl)-1H-benzoldlimidazole F F
Y-F

,11.0 y' HN
N CI

This compound was prepared by essential the similar method as of example 76 to afford the product as a white solid, MS (+) ES: 543 (M+H) .

Example 105 Preparation of 2-(4-((iso-propyl)sulfonyl)pheny1)-2-(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo [di imidazol-2-yDethanol F F
Y-F

,11.0 ) ' = HN 40, N CI
OH

This compound was prepared by essential the similar method as of example 77 to afford the product as a white solid, MS (+) ES: 573 (M+H) .
Example 106 Preparation of (4-((iso-propyl)sulfonyl)phenyl)(4,6-dichloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo [di imidazol-2-yl)methanol F F
Y-F

g,o HN
N CI
OH

This compound was prepared by essential the similar method as of example 78 to afford the product as a white solid, MS (+) ES: 559 (M+H) .
Example 107 Preparation of 2-(4,6-dichloro-5-(2-(trifluoromethyl)pheny1)-1H-benzoldlimidazol-2-y1)-2-(4-((isopropylsulfonyl)phenyl)ethanol os-=
CI =

This compound was prepared by essential the same method as of example 4 to afford the product as a white solid, MS (+) ES: 557 (M+H) .

Example 108 Preparation of 2-(4-(ethylsulfonyflbenzy1)-4,6-difluoro-5-(2-(trifluoromethoxy)pheny1)-1H-benzoldlimidazole F, ?F
FO

=
HN
N F

02N Br Fe/AcOH H2N F
H2N io F (TfC0)20 Me0H
KNO3 HN ON Br K2CO3 Br H2N F EDCI,HOBt N HOAG
H2N Br DMF

Br ON

y¨F
FO

SUZUKI 11.0 F Br F * NH ,p HN
F
Step 1. Preparation of N-(4-bromo-3,5-difluoro-2-nitropheny1)-2,2,2-trifluoroacetamide F)<FrO

m Br Br KNO3 was added into a cooled (ice-water) solution of 4-bromo-3.5-difluoroaniline (2 g, 0.01 mol) in trifluoroacetic acid anhydride (10 ml) in one portion. Then the reaction mixture was allowed to worm-up to room temp with stirring overnight. The solvent was evaporated to dryness and the residue was treated with ethyl acetate, washed with sat.
sodium bicarbonate solution, water, dried over MgSO4. The solid was filtered off and the solvent was evaporated. The product was purified by flash chromatography with hexane/ethyl acetate to afford a off-white solid (1.8 g, 51%), MS (+) ES: 349 (M+H) .

Step 2. Preparation of 4-bromo-3,5-difluoro-2-nitroaniline F)CFr H2N so F
HN F
ON Br 02N Br A mixture of K2CO3 (0.95 g, 6.9 mmol) and N-(4-bromo-3,5-difluoro-2-nitropheny1)-2,2,2-trifluoroacetamide (2 g, 5.7 mmol) in methanol (20 ml) was heated to 50 C for 3 h.
After cooling, water (50 ml) was added and the precipitate was collected by filtration, washed thoroughly with water and dried in vacuum to afford the product as a off-white solid (1.4 g, 98%) which was used directly to the next step without purification, MS (+) ES:
253 (M+H) .
Step 3. Preparation of 4 -bro mo-3 ,5 -diflu orobenzene- 1,2-diamine 02N Br H2N Br To a stirred mixture of AcOH (50 ml) and Et0H (100 ml) was suspended 4-bromo-3,5-difluoro-2-nitroaniline (2.5 g, 0.01 mol) and iron powder (4.4 g, 0.08 mol).
The reaction was heated slowly to reflux and allowed to stir for 1 hour. The reaction was cooled to room temperature then diethyl ether (50 ml) and water (50 ml) was added. The solution was carefully neutralized by the addition of sodium carbonate. The combined organic extracts were washed with saturated NaHCO3 (2.x.30 ml), H20 (2.x.30 ml) and brine (1.x.30 ml) then dried over Na2SO4, filtered and concentrated to dryness under vacuum to yield the title compound as a white solid (1.6 g, 71%), MS (+) ES: 223 (M+H) .
Step 4. Preparation of N-(6-amino-3-bromo-2,4-difluoropheny1)-2-(4-(ethylsulfonyl)phenyl)acetamide 11.0 H2N Br Br NH 140 1-Ethyl-(3-(3-dimethylamino)propy1)-carbodiimide hydrochloride (2.0 g, 0.01mol) and benzotriazol-l-ol (1.35 g, 0.01mol) were added into a cooled solution (ice-water bath) of 4-bromo-3 ,5-difluorobenzene-1,2-diamine (2.2 g, 0.01 mol) and 2-(4-(ethylsulfonyl)phenyl)acetic acid (example 1, step 3, 2.28 g, 0.01 mol) in DMF
(10 ml) portion-wise over 30 mm. After the addition was completed, the mixture was stirred for 60 mm at 0-5 C, and then was allowed to warm-up to room temp with stirring overnight. The mixture was partitioned between water (50 ml) and ethyl acetate (50 ml). The organic phase was separated and dried over MgSO4, filtered. The solvent was evaporated under reduced pressure to leave a off-white solid that was purified by flash chromatography with hexane/ethyl acetate to afford the product as a solid (3.5 g, 80%), MS (+) ES:
433 (M+H) .
Step 5. Preparation of 5 -bro mo-2- (4-(ethylsu lfonyl)b enz y1)-4 ,6-diflu oro -1H-benzoldlimidazole L o ID
cnociN so F HOAc Br ref Im Br N lb) N-(6-amino-3-bromo-2,4-difluoropheny1)-2-(4-(ethylsulfonyl)phenyl)acetamide (step 4) (3.5 g, 0.0075 mol) was mixed with acetic acid (25 ml) and the mixture was heated to 100 C
for 4 hours, cooled. The solvent was evaporated under reduce pressure and the residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate, dried over MgSO4. This product was purified by flash chromatography with hexane/ethyl acetate to afford the product as a white solid (2.8 g, 85%), MS (+) ES: 415 (M+H) .
Step 6. Preparation of 2-(4-(ethylsulfonyl)benzy1)-4,6-difluoro-5-(2-(trifluoromethoxy)phenyl)-1H-benzo [di imid azole ,o F
(2)S' Fl N F Br Pc12(dba)32, [(t-Bu3i N)PH] BF4.. *
=
, *
A mixture of 5 -bromo -2- (4 -(ethyl su lfo nyl)benzy1)-4 ,6-difluoro-1H-benzo [di imid azole (42 mg, 0.1 mmol), 2-trifluoromethoxyphenylboronic acid (62 mg, 0.003 mol), tris-(dibenzylideneacetone)dipalladium(0) (6 mg), tri(tert-butyl)phosphonium tetrafluoroboronate (6 mg) and sodium carbonate (2M solution, 0.2 ml) in 1,4-dioxane (0.5 ml) was degassed, sealed and heated to 100 C under Microwave irradiation for lh. The volatile solvents were removed under reduced pressure. The residue was directly loaded onto a flash solid cartridge and flash chromatographied with hexane/ethyl acetate to afford a white solid product (34 mg, 68% yield), MS (+) ES: 497 (M+H) .
Example 109 Preparation of 2 -(4 ,6 -difluoro-5 - (2- (trifluoromethoxy)pheny1)- 1H-benzo [di imid azol-2- y1)-2-(4-(ethylsulfonyl)phenyl)ethanol F F
F 0)LF
(i 0 HN
F
= H

This compound was prepared by essential the similar method as of example 77 to afford the product as a white solid, MS (+) ES: 527 (M+H) .
Example 110 Preparation of (4,6-difluoro-5-(2-(trifluoromethoxy)pheny1)-1H-benzokllimidazol-2-y1)(4-(ethylsulfonyl)phenyl)methanol F F
FO
(i 0 HN
N F
OH

This compound was prepared by essential the similar method as of example 78 to afford the product as a white solid, MS (+) ES: 513 (M+H) .
Example 111 Preparation of 2-(4-(ethylsulfonyflbenzy1)-4,6-difluoro-5-(2-(trifluoromethyl)phenyl)-1H-benzoldlimidazole ,11.0 HNQO
N F

This compound was prepared by essential the same method as of example 91, except by using 2-trifluoromethylphenylboronic acid instead of 2-trifluoromethoxyphenylboronic acid in step 6, to afford the product as a white solid, MS (+) ES: 481 (M+H) .
Example 112 Preparation of 2-(4,6-difluoro-5-(2-fluoropheny1)-1H-benzokllimidazol-2-y1)-2-(4-(ethylsulfonyl)phenyl)ethanol F F

HN
N F
OH

This compound was prepared by essential the similar method as of example 92 to afford the product as a white solid, MS (+) ES: 461 (M+H) .
Example 113 Preparation of (4,6-difluoro-5-(2-methoxypheny0-1H-benzoldlimidazol-2-y1)(4-(ethylsulfonyflphenyl)methanol Liõo H N 41, OH

This compound was prepared by essential the similar method as of example 93 to afford the product as a white solid, MS (+) ES: 459 (M+H) .
Example 114 Preparation of 2-(4,6-difluoro-5-pheny1-1H-benzokllimidazol-2-y1)-2-(4-(ethylsulfonyl)phenyl)ethanol )!O
HN
N F
OH

This compound was prepared by essential the similar method as of example 92 to afford the product as a white solid, MS (+) ES: 443 (M+H) .
Example 115 Preparation of 2-(4-(ethylsulfonyl)benzyl)-4,6-dimethyl-5-(2-(trifluoromethyl)pheny1)-1H-benzoldlimidazole F3c /1\1 .0 Cr'S
Pd2(dba)3, [(t-Bu3)PH]BF4 F3C
Br i& aq. Na2CO3, dioxane 11' i&
N N
This compound was prepared by the same procedure as described in example 108 to afford the product as a white solid, MS (+) ES: 473 (M+H) .
Example 116 Preparation of 2-(4,6-dimethy1-5-(2-(trifluoromethyl)pheny1)-1H-benzokllimidazol-2-y1)-2-(4-(ethylsulfonyl)phenyl)ethanol F3c o HN
OH

This compound was prepared by essential the similar method as of example 77 to afford the product as a white solid, MS (+) ES: 503 (M+H) .
Example 117 Preparation of 2-(4-(ethylsulfonyl)pheny1)-2-(5-(2-methoxypheny1)-4,6-dimethyl-benzokllimidazol-2-yDethanol =HN
OH

This compound was prepared by essential the similar method as of example 77 to afford the product as a white solid, MS (+) ES: 465 (M+H) .

Example 118 Preparation of (4-(ethylsulfonyl)phenyl)(5-(2-methoxypheny1)-4,6-dimethyl-1H-benzo [di imidazol-2-yl)methanol HN
N
OH

This compound was prepared by essential the similar method as of example 78 to afford the product as a white solid, MS (+) ES: 451 (M+H) .
Example 119 Preparation of 2-(6-chloro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo [di imidazol-2-y1)-2-(4-.. (ethylsulfonyl)phenyl)ethanol ,11.0 op HN
HO

This compound was prepared by essential the similar method as of example 4 to afford the product as a white solid, MS (+) ES: 525 (M+H) .
Example 120 Preparation of 2-(4-(ethylsulfonyl)pheny1)-2-(6-fluoro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo[d] imidazol-2-yDethanol FO

=
HN
HO

This compound was prepared by essential the similar method as of example 4 to afford the product as a white solid, MS (+) ES: 509 (M+H) .

Example 121 Preparation of (4-(ethylsulfonyl)phenyl)(6-fluoro-5-(2-(trifluoromethoxy)pheny1)-1H-benzo[d]imidazol-2-y1)methanol F F
Y-F
FO
=/S' 0 HN * It N
OH

5 This compound was prepared by essential the similar method as of example 2 to afford the product as a white solid, MS (+) ES: 495 (M+H) .
Example 122 Preparation of N-cyclopropy1-44(4,6-dichloro-5-(2-(trifluoromethoxy)pheny0-1H-10 benzo [di imidazol-2-yl)methyl)benzenesulfonamide F
)7F

A, g,o N CI

9 ¨NH2 it, on I A
0 01s031-1 0 s, HO 0 C to it HO CH2C12/DIPEA Ho CI
o ci..T., o NH2 A 11,0 CI
AcOH a ..,,0 BrA'eLNH2 L-\--, ,S' Br II' 00 HN 11 Br CI N 0 ___________ 3.
H
____________ 3. N CI
EDCl/HOBt/DMF N CI refluxing H

OH F
/
..., )TF
H F
X¨F 0 CI 0 F

Pd2(dba)3, Kt-Be3)PHBF4 AN A,c) HN _... H
N CI
_______________ 3. H
aq N Na2CO3, dioxane Na0Et/DMS0 N CI HO
MV 100 C, 60min Step 1. Preparation of 2-(4-(chlorosulfonyl)phenyl)acetic acid o II

0 8'CI
_0...
HO I.1 0 C to rt HO

To chlorosulfonic acid (35 ml) was dropped 2-phenylacetic acid (5 g, 36.724 mmol) at 0 C, and the reaction mixture was stirred at 0 C for 1 hour and then at room temperature over night. After the reaction was completed, the reaction mixture was slowly cooled to 0 C
and poured on to ice carefully. The resulting solid was extracted with ethyl acetate (3X10 mL) and dried over MaSO4. The solid was filtered off and the solvent was evaporated under reduced pressure to leave a off-white solid to give the target compound (6.8 g, 78%), MS (+) ES: 235 (M+H) .
Step 2. Preparation of 2-(4-(N-cyclopropylsulfamoyl)phenyl)acetic acid ¨NH2 rt, on 0 g, A
0 =6-0, _______________________________________ 0 õ N

To a stirred solution of 2-(4-(chlorosulfonyl)phenyl)acetic acid (234 mg, 1.0 mmol) and i-Pr2NEt (0.52 mL, 2.86 mmol) in CH2C12 (10 mL) was added cyclopropylamine (0.076 mL, 1.1 mmol). The mixture was stirred overnight at rt, diluted with Et0Ac (80 mL), washed with 5 percent aq HC1 (2 x 10 mL) and brine (10 mL), and dried over Mg2SO4. Removal of the solvent left the product as a gummy solid (180 mg, 70%). MS (+) ES: 256 (M+H) .
Step 3. Preparation of N- (2- amino-4 -bro mo-3 ,5 -dichloropheny1)-2 - (4- (N-c yc loprop ylsulfamo yl)phenyl) acetamide O ciy-,rNH2 ii A Br A
NH2 õ.
CI Br OH H
EDCl/HOBt/DMF
40 so HO CI

To 2-(4-(N-cyclopropylsulfamoyl)phenyl)acetic acid (255 mg, 1 mmol) in DMF was added 4-bromo -3,5 -dichlorobenzene- 1 ,2-diamine (255 mg, lmmol), HOB t(135 mg, lmmol), triethylamine (202mg, 2 mmol), followed by the addition of EDCI (191 mg, 1 mmol) at 0 C.
The mixture was stirred at 0 C for 30 mm and was allowed to reach room temperature and stirred over night. The reaction solution was partitioned between ethyl acetate (15 ml) and water (15 ml). The organic phase was separated and dried over MgSO4 Evaporation of the solvent to leave a tan solid that was directly used for the next step without purification (490 mg, 99% yield), MS (+) ES: 492 (M+H) .
Step 4. Preparation of4-((5-bromo-4,6-dichloro-1H-benzo [di imid azol-2-yl)methyl)-N-ethylbenzenesulfinamide A cd,0 CICI
CI
AcOH 0 0 Br HN Br refluxing N' *
CI
NH, N- (2-amino-4-bro mo -3 ,5 -dichloropheny1)-2- (4 -(N-c ycloprop ylsulfamo yl)phenyl) acetamide (490 mg, 1 mmol) in acetic acid (5 ml) was heated to 80 C for 3 h. After cooling, the solvent was evaporated to dryness and dissolved in ethyl acetate 910 ml), washed with saturated sodium bicarbonate solution and brine, dried over MgSO4. Evaporation of the ethyl acetate to leave a solid that was purified with flash chromatography with solvent hexane/ethyl acetate (containing 10% Me0H), to afford the product as a white solid 288 mg (60% yield), MS (+) ES: 474 (M+H) .
Step 5. Preparation of N-c ycloprop y1-4 ,6-dichloro-5 - (2- (triflu oro methoxy)pheny1)- 1 H-benzo[d] imidazol-2-yl)methyl)benzenesulfonamide (example 164) OH
=
B, OH

N4 HN A, g,0 411 Br Pd2(dba)3 [(f-Bu3)PH]l3F4 NSJ
HN
I
aq Na2CO3 dioxane N CI N CI
MV 100 C, 60min A
mixture of 4-((5 -bromo-4,6-dichloro-1H-benzo [di imidazol-2 - yl)methyl)-N-cyclopropylbenzenesulfinamide (step 4) (238 mg, 0.5 mmol), 2-trifluoromethoxyphenylboronic acid (308 mg, 1.5 mmol), tris-(dibenzylideneacetone)dipalladium(0) (24 mg), tri(tert-butyl)phosphonium tetrafluoroboronate (24 mg) and sodium carbonate (1 ml, 2M solution) in 1,4-dioxane (2.5 ml) was degassed, sealed and heated to 100 C under Microwave irradiation for lh. The volatile solvents were removed under reduced pressure. The residue was directly loaded onto a ISCO solid cartridge and flashed with hexane/ethyl acetate to afford a white solid product 83 mg (30% yield), MS (+) ES: 556 (M+H) .
Example 123 Preparation of N-cycloprop y1-4- (1 - (4 ,6-dichloro -542- (triflu oromethoxy)pheny1)- 1 H-b enzo[d] imidazol-2- y1)-2 -hydro xyethyl)benzenesulfo namide F
CI O)V
ms HN
-NI CI

X-F

AN g*0 AN g,0 NS HN NS

HN
N CI N CI
HO

To N-c yc loprop y1-4- ((4 ,6-dichloro-5 -(2- (trifluorometho xy)pheny1)- 1H-benzoldlimidazol-2-yflmethyflbenzenesulfonamide (5.7 mg, 0.01 mmol) in DMSO
(0.05 ml) was added paraformaldehyde (0.6 mg, 0.02 mmol), followed by the addition of sodium ethoxide (1.3 mg, 0.002 mmol) at room temperature. The reaction mixture was stirred for 60 mm and by directly by Prep HPLC with elution system C to afford the product as a white solid 3.8 mg (66% yield), MS (+) ES: 586 (M+H) .
Example 124 Preparation of 2-(6-chloro-5-(2-isopropoxypheny1)-1H-benzokllimidazol-2-y1)-2-(4-((cyclopropylmethyl)sulfonyl)phenyl)ethanol A j,0 HN

Step 1. Preparation of cyclopropylmethyl 2-(4-((cyclopropylmethyl)thio)phenyl)acetate HS
Br SH
To a solution of (4-mercaptophenyl) acetic acid (3.4 g, 0.02 mol) in N, N-dimethylformamide (DMF) (20 ml) was added K2CO3 (11 g, 0.08 mol) and (bromomethyl)cyclopropane (8.1 g, 0.06 mol). The reaction mixture was stirred at RT. After 2,5 hours, the starting material was totally consumed. The reaction mixture was partitioned between ethyl acetate (30 ml) and water (30 ml). The organic phase was washed with water (30 ml) and brine (20 ml), dried over sodium sulphate, filtered, and concentrated to give the desired product. %), MS (+) ES: 277 (M+H) .
Step 2. Preparation of cyclopropylmethyl 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)acetate cH2oI2 rv=
To a 250 ml round bottom flask, were added cyclopropylmethyl 2-(4-((cyclopropylmethyl)thio)phenyl)acetate (6.76 g, 0.0245 mol) and dichloromethane (82.5 ml). The reaction mixture was cooled to 0 C. To the same flask, m-chloroperbenzoic acid (12.6 g, 0.073 mol) was added at 0 C. The reaction mixture was stirred at room temperature for 12 h. The resulting suspension was filtered through a pad of celite. The filtrate was washed with water. The organic layer was separated, washed with saturated sodium .. bicarbonate solution three times, followed by brine and dried over anhydrous sodium sulfate.
The solvent was evaporated under reduced pressure to get the crude product.
The crude product was purified by flash column chromatography with hexane/ethyl acetate to get the title compound as oil, MS (+) ES: 309 (M+H) Step 3. Preparation of 2-(4-((cyclopropylmethyl)sulfonyl)phenyllacetic acid 1 KOH/Me0H HO

To a 50 mL round bottom flask, were added cyclopropylmethyl 2-(4-((cyclopropylmethyl)sulfonyl)phenyllacetate (3.08 g, 0.01 mol) and ethanol ( 18 ml). To the same flask, a solution of sodium hydroxide in water (1.42 g, 0.0355 mol in 18 ml of water) was added. The reaction mixture was stirred at room temperature for 12 h. The volatiles were evaporated under reduced pressure. The residue was acidified with IN HC1 to pH
5.0 and extracted with ethyl acetate (15 ml X 3). The organic layer was separated and combined, washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to get the title compound as a colorless oil that was solidified upon standing (85%).
MS (+) ES: 255 (M+H) .
Step 4. Preparation of N-(2-amino-5-bromo-4-chloropheny1)-2-(4-((c yc loprop ylmethyl) su lfonyl)phenyl) acet amide o H2N CI I>_/= 0 OH p ,S' 62N CI
H2N Br 0' 10 Br =
EDCI HOBt DMF
1-Ethyl-(3-(3-dimethylamino)propy1)-carbodiimide hydrochloride (2.0 g, 0.01 mol) and hydroxybenzotriazol-l-ol (1.35 g, 0.01 mol) were added into a cooled solution (ice water bath) of 4-bromo-5-chlorobenzene-1,2-diamine (2.21 g, 0.01 mol) and 2-(4-((cyclopropylmethyl)sulfonyl)phenyllacetic acid (step 3, 2.54 g, 0.01 mol) in DMF (10 ml), portion wise over 30 mm. After the addition was completed, the mixture was stirred for 60 mm and was allowed to warm-up to room temp, stirred overnight. The mixture was partitioned between water (50 ml) and ethyl acetate (50 m1). The organic phase was separated and dried over MgSO4, filtered. The solvent was evaporated under reduced pressure to leave an off-white solid which was purified by flash chromatography with hexane/ethyl acetate to afford the product as an off-white solid (75%), MS (+) ES: 457 (M+H) .
Step 5. Preparation of 5 -bro mo-6-chloro -2- (4 -((cycloprop ylmethyl) su lfonyl)b enz y1)- 1H-benzo dIimidazole >s0 82N CI HOAc 6' Br heating /N Br CI
N-(2-amino-5 -bro mo -4-chloropheny1)-2 - (4- ((c ycloprop ylmethyl) sulfo nyl)phenyl) acetamide (step 4) (3.42 g, 7.5 mmol) was mixed with acetic acid (25 ml) and the mixture was heated to 80 C for 4 hours, cooled. The solvent was evaporated under reduce pressure and the residue was dissolved in Et0Ac and washed with saturated sodium bicarbonate, dried over MgSO4.
This product was purified by flash chromatography with hexane/ethyl acetate to afford the product as a white solid 2.6 g (80%), MS (+) ES: 439 (M+H) Step 6. Preparation of 6 -chloro-2 -(4- ((c yc loprop ylmethyl) su lfo nyl)benz y1)-5 - (2 -isopropoxypheny1)- 1H-benzo [di imid azole s-N Br Pd2(dba)3, [(t-Bu3)P1-11BF4 /

Na CO dioxane 2 3, CI NCI
A
mixture of 5-bromo-6-chloro-2 - (4- ((c ycloprop ylmethyl) sulfo nyl)benzy1)-benzoldlimidazole (step 5) (439 mg, 1 mmol), (2-isopropoxyphenyeboronic acid (495 mg, 3 mmol), tris-(dibenzylideneacetone)dipalladium(0) (60 mg), tri(tert-butyl)phosphonium tetrafluoroboronate (60 mg) and sodium carbonate (2 ml ml, 2M solution) in 1,4-dioxane (8 ml) was degassed, sealed and heated to 100 C under Microwave irradiation for 60 mm. The volatile solvents were removed under reduced pressure. The residue was directly taken into DCM and loaded onto an ISCO solid cartridge and flashed with hexane/ethyl acetate to afford a white solid product 355 mg (72% yield), MS (+) ES: 495 (M+H) .

Step 7. Preparation of 2-(6-chloro-5-(2-isopropoxypheny1)-1H-benzoldlimidazol-2-y0-2-(4-((cyclopropylmethyl)sulfonyl)phenyl)ethanol CI o ci o ,k),O
HN
HN
HO
6-chloro-2-(4-((cycloprop ylmethyl) su lfonyflb enz y1)-5 -(2-isopropo xypheny1)- 1H-benzoldlimidazole (49.5 mg, 0.1 mmol) was dissolved in 1 ml anhydrous DMSO, paraformylaldehyde (6 mg, 0.2 mmol) wan added with stirring, followed by the addition of powder sodium ethoxide (12 mg, 0.2 mmol). The mixture was stirred at room temp for 60 mm. (Check LCMS for completion). The mixture then was treated with Et0Ac (10 ml) and washed with sat. NH4C1 solution, followed by water. The organic phase was dried with MgSO4. The product was purified by flash chromatography with hexane/Et0Ac (10%

NH3 in Me0H) to afford a white solid 37 mg (70% yield example 124). MS (+) ES:

(M+H) .
Examples 124-1 and 124-2 Preparation of (S)-2-(6-chloro-5 -(2-isopropoxypheny1)-1H-benzo [di imid azol-2- y1)-2-(4-((cyclopropylmethyl)sulfonyl)phenyl)ethanol (example 124-1) and (R)-2 - (6-chloro-5- (2-isopropoxyp heny1)- 1H-b enzo [d] imidazol-2 - y1)-2 -(4-((cyclopropylmethyl)sulfonyl)phenyl)ethanol (example 124-2) CI o a o Ag,o HN
HN
(s) N
(R) HO
HO
Example 124 was separated chirally (separation conditions: Dasail 20*200mm,5um;
mobile phase : ethanol/hexane=1:4 (v/v); flow rate: 30 mL/min), The corresponding fractions were collected and concentrated under reduced pressure to obtain the title compounds (400 mg, 400 mg).
Single configuration compound (the shorter retention time) MS (+) ES: 525 (M+H) Chiral HPLC analysis: retention time 6.296 minutes, chiral purity: 100%
(chromatographic column: OZ Phenomenex Lux Cellulose-2 150*4.6mm,5um; mobile phase:
ethanol/hexane=3:2 (v/v));
1H NMR (400 mHz, DMSO-d6): 12.53 (s, 1H), 7.87 (d, 8.0 Hz, 2 H), 7.71 (s, 0.6 H) (due to .. benzoimidazole taumeriazation), 7.67 (d, 12.0 Hz, 2 H), 7.57 (s, 0.4 H), 7.43 (s, 0.48 H), 7.34(t, 8.0 Hz, 1 H), 7.31 (s, 0.44 H),7.16-7.11 (m, 1 H), 7.08 (d, 8.0 Hz, 1 H), 6.98 (t, 8.0 Hz, 1 H), 5.16 (t, 4.0 Hz, 1 H), 4.59-4.43 (m, 2 H), 4.29-4.15 (m, 1 H), 4.06-3.95 (m, 1 H), 3.23 (d, 8.0 Hz, 2H), 1.12 (d, 4.0 Hz, 6 H), 0.89-0.75 (m, 1 H), 0.49-0.39 (m, 2 H), 0.18-0.09 (m, 2 H).
Single configuration compound (the longer retention time) MS (+) ES: 525 (M+H) Chiral HPLC analysis: retention time 11.837 minutes, chiral purity: 98.875%
(chromatographic column: OZ Phenomenex Lux Cellulose-2 150*4.6mm,5um; mobile phase:
ethanol/hexane=3:2 (v/v);
1H NMR (400 mHz, DMSO-d6): 12.53 (s, 1H), 7.87 (d, 8.0 Hz, 2 H), 7.71 (s, 0.6 H) (due to benzoimidazole taumeriazation), 7.67 (d, 12.0 Hz, 2 H), 7.57 (s, 0.4 H), 7.43 (s, 0.48 H), 7.34(t, 8.0 Hz, 1 H), 7.31 (s, 0.44 H),7.16-7.11 (m, 1 H), 7.08 (d, 8.0 Hz, 1 H), 6.98 (t, 8.0 Hz, 1 H), 5.16 (t, 4.0 Hz, 1 H), 4.59-4.43 (m, 2 H), 4.29-4.15 (m, 1 H), 4.06-3.95 (m, 1 H), 3.23 (d, 8.0 Hz, 2H), 1.12 (d, 4.0 Hz, 6 H), 0.89-0.75 (m, 1 H), 0.49-0.39 (m, 2 H), 0.18-0.09 (m, 2 H).
Example 125 Preparation of 4 ,6-dichloro-5 -(4,4-diflu oropip eridin- 1 - y1)-2-(4-(ethylsulfo nyl)b enzy1)- 1H-benzold] imidazole CI
J(:) HN
\iF
/.\ F
CI

Step 1. Preparation of 2,4-dichloro-3 -(4,4 -difluoropiperidin- 1 - y1)-6-nitro aniline CI i& NO2 DMSO FJ
CI

The mixture of 2,3,4-trichloro-6-nitroaniline (241mg, 1 mmol), 4,4-difluoropiperidine (190 mg, 1.2 mmol) and DIEA (390 mg, 3 mmol) in 8 ml DMSO was heated in a sealed vessel to 108 C over night. After cooling, the reaction mixture was partitioned between water (30 ml) and ethyl acetate (10 m1). The organic phase was separated and dried over MgSO4. The solid was filtered off and the solvent was evaporated, the residue was directly flashed with hexane/ethyl acetate to afford a yellow solid 280 mg (yield 85%), MS (+) ES:
326 (M+H) .
5tep2. Preparation of 3,5 -dichloro-4 - (4,4 -difluoropiperidin- 1 -yl)benzene-1,2-diamine CI ioNO2 c, NH2 CI CI
The mixture of 2,4 -dichloro -3 -(4 ,4-diflu oropip eridin- 1 - y1)-6-nitro aniline (200 mg, 0.68 mmol), and Pd/C (20 mg) in 15 ml methanol was hydrogenated with a nitrogen balloon for 2h. The catalyst was filtered off and the solvent was evaporated to leave tan residue that was directly flashed with hexane/ethyl acetate to afford an oil product 120 mg (yield 66%), (MS
(+) ES: 296 (M+H) .
Step 3. Preparation of 4 ,6-dichloro-5 -(4,4-difluoropiperidin-1- y1)-2-(4-(ethylsulfonyl)benzyl)-1H-benzo [di imidazole 0 0 \e-µ
HO 41, ci Is NH2 ci N\
="*--*'N NH2 CI
CI
1-Ethyl-(3-(3-dimethylamino)propy1)-carbodiimide hydrochloride (20 mg, 0.1 mmol) and hydroxybenzotriazol-1-ol (13.5 mg, 0.1 mmol) were added into a cooled solution (ice water bath) of 3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)benzene-1,2-diamine (29.6 mg, 0.1 mmol) and 2-(4-(ethylsulfonyl)phenyl)acetic acid (22.8 mg, 0.01 mmol) in DMF
(1 ml).
After the addition was completed, the mixture was stirred and allowed to warm up to room temp, stirred overnight. The mixture was partitioned between water (50 ml) and ethyl acetate (50 ml). The organic phase was separated and dried over MgSO4, filtered. The solvent was evaporated under reduced pressure to leave an off-white solid which was mixed with acetic acid (1 ml). The mixture was heated to 80 C for 2 hours, cooled. The solvent was evaporated under reduce pressure and the residue was dissolved in Et0Ac and washed with saturated sodium bicarbonate, dried over MgSO4. This product was purified by flash chromatography with hexane/ethyl acetate to afford the product as a white solid 26 mg (60%), MS (+) ES: 488 (M+H) .
Example 126 Preparation of 2-(5 ,7 -dichloro -6- (4 ,4-difluoropiperidin- 1 - y1)- 1H-benzo [di imid azol-2- y1)-2-(4-(ethylsulfonyl)phenyl)ethanol a \N N
F/\ W I
CI N

Step 1. Preparation of 2,3 ,4-Trichloro-6-nitrob enzenamine Cl CI
A suspension of 4,5-dichloro-2-nitrobenzenamine (30 g, 145 mmol) and N-chlorosuccinimide (24.2 g, 181.2mm01) in 250 mL of DMF was stirred at 100 C
for 2 hours.
It was cooled to room temperature, and poured into ice-cooled water (1 mL).
The precipitate formed was collected by filtration. It was dissolved in dichloromethane and washed with water. The organic layer was concentrated to get 2,3,4-trichloro-6-nitrobenzenamine (34.2 g, 97.5 % yield) as a brightly yellow solid Step 2. Preparation of 2 ,4-dichloro-3 -(4,4-difluoropip eridin-1- y1)-6-nitrobenzenamine CI NO

NH

CI
A solution of 2,3,4-trichloro-6-nitrobenzenamine (5 g, 20.7 mmol), N,N-diisopropyl ethylamine (11.8 mL, 62.1 mmol), and 4,4-difluoropiperidine (3.8 g, 31.06 mmol) in 20 mL
of DMF was stirred at 105 C over the weekend. The reaction solution was absorbed onto 20 g of silica gel, loaded to a silica gel column, and eluted with 30% ethyl acetate in hexanes, to get the 2,4-dichloro-3-(4,4-difluoropiperidin-1-y0-6-nitrobenzenamine (4.72 g, 70.0 % yield) as a brightly yellow solid MS (+) ES: :326(M+H) .
Step 3. Preparation of 3,5-Dichloro-4-(4,4-difluoropiperidin-1-Abenzene-1,2-diamine -I." NH2 F.--ej NH2 CI F CI
To a solution of 2,4-dichloro-3-(4,4-difluoropiperidin-1-y1)-6-nitrobenzenamine (3.5 g, 10.8 mmol) in 30 mL of THF was added zinc powder (7 g) and concentrated hydrochloric acid (2mL). The reaction mixture was stirred at room temperature overnight. It was filtered. The filtrate was concentrated, and purified on a silica gel column, eluting with ethyl acetate, to get 3,5-dichloro-4-(4,4-difluoropiperidin-1-Abenzene-1,2-diamine (1.85 g, 57.8 %
yield) as a pale solid MS (+) ES: 296 (M+H) Step 4. Preparation of N-(6-amino-2,4-dichloro-3-(4,4-difluoropiperidin-1-y0pheny1)-2-(4-(ethylsulfonyl)phenyl)acetamide and N-(2-amino-3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)pheny1)-2-(4-(ethylsulfonyl)phenyeacetamide * NH2 a NH2 CI N
0.,*0 CI
CI 0 and To a solution of 3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)benzene-1,2-diamine (350 mg, 1.18 mmol) and 2-(4-(ethylsulfonyl)phenyl)acetic acid (225 mg, 0.99 mmol) in dichloromethane (10 mL) was added EDCI (285 mg, 1.49 mmol) and HBTU (565 mg, 1.49 mmol). The reaction solution was stirred at room temperature for 2 hours. It was absorbed onto 5 g of silica gel, and loaded onto a silica gel column. The column was eluted with 45 %
of ethyl acetate in hexanes to get a mixture of N-(2-amino-3,5-dichloro-4-(4,4-difluoropiperidin-1-Apheny1)-2-(4-(ethylsulfonyl)phenyeacetamide and N-(6-amino-2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)pheny1)-2-(4-(ethylsulfonyephenyl)acetamide (410 mg, 81.8 % yield) as a white solid MS (+) ES: 506 (M+H) .
Step 5. Preparation of 2-(4-(Ethylsulfonyl)benzy1)-4,6-dichloro-5-(4,4-difluoropiperidin-1-y1)-1H-benzoldlimidazole CI C) * NH2 0, ,C) CI io N CI
NH
_Cy NH2 0 1,p CI
0' 0 CIO
and F CI H
The mixture of N-(2- amino -3 ,5 -dichloro -4-(4,4 -difluoropiperidin-1 -yl)pheny1)-2 -(4-(ethylsulfonyl)phenyl)acetamide and N-(6-amino-2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)pheny1)-2-(4-(ethylsulfonyl)phenyeacetamide (410 mg) obtained from the previous step was treated with 15 mL of glacial acetic acid at 80 C for 2 hours. It was concentrated, and purified on a silica gel column, eluting with 60 % ethyl acetate in hexanes, to get 2-(4-(ethylsulfonyl)benzy1)-4,6-dichloro-5-(4,4-difluoropiperidin-1-y1)-1H-benzo [di imidazo le (375 mg, 94.8 % yield) as a pale solid MS (+) ES: 488(M+H) .
Step 6. 2-(5,7-dichloro-6-(4,4-difluoropiperidin-1-y1)-1H-benzo [di imidazol-2 - y1)-2-(4-(ethylsulfonyl)phenyl)ethanol /0 a o.
ci -s r\,1 CN Nµj a H
H
OH
To a solution of get 2-(4-(ethylsulfonyl)benzy1)-4,6-dichloro-5-(4,4-difluoropiperidin-1-y1)-1H-benzoldlimidazole (20 mg, 0.04 mmol) and paraformaldehyde (6.3 mg, 0.21 mmol) in 3 mL of DMSO, was added sodium ethwdde (8.2 mg, 0.12 mmol). The reaction solution was stirred at room temperature for 2 hours. Then, it was directly loaded to a reverse phase column with elution system D, and purified to get 2-(4,6-dichloro-5-(4,4-difluoropiperidin-1-y1)-1H-benzoldlimidazole-2-y1)-2-(4-(ethylsulfonyl)phenyl)ethanol (9 mg, 42.5 % yield) as a white solid; MS (+) ES: 518 (M+H) .
Examples 126-1 and 126-2 Preparation of (R)-2-(5,7-dichloro-6-(4,4-difluoropiperidin-1-y1)-1H-benzo [di imid azol-2- y1)-2-(4-(ethylsulfonyl)phenyl)ethanol (Example 126-1) and (S)-2-(5,7-dichloro-6-(4,4-difluoropiperidin-1-y1)-1H-benzo [di imid azol-2-y1)-2-(4-(ethylsulfonyl)phenyl)ethanol (Example 126-2) (34 / N
_________________________________________ N
N CI N
H=
OH OH

Example 126 was separated chirally (separation conditions: cellulose-1 20*250mm,5um;
mobile phase : ethanol/hexane=1:4 (v/v); flow rate: 20 mL/min), The corresponding fractions were collected and concentrated under reduced pressure to obtain the title compounds (420 mg, 410 mg).
Single configuration compound (the shorter retention time) MS (+) ES: 518 (M+H)+;
Chiral HPLC analysis: retention time 7.275 minutes, chiral purity: 100%
(chromatographic column: OD Phenomenex Lux Cellulose-1 150*4.6mm, Sum; mobile phase:
ethanol/hexane=15:85 (v/v);
1H NMR (400 mHz, CD30D): 7.90 (d, 8.0Hz, 2 H), 7.67(d, 8.0 Hz, 2 H), 7.62 (s, 0.5 H), 7.49 (s, 0.5 H), 4.59 (t, 8.0 Hz, 1 H), 4.38 (dd, 8.0, 11.0 Hz, 1 H), 4.27-4.11 (m, 1 H), 3.44-3.28 (m, 4 H), 3.20 (q, 8.0 Hz, 2 H), 2.24-2.01 (m, 4H), 1.21 (t, 8.0 Hz, 3 H).
Single configuration compound (the longer retention time) MS (+) ES: 518 (M+H)+;
Chiral HPLC analysis: retention time 9.290 minutes, chiral purity: 100%
(chromatographic column: OD Phenomenex Lux Cellulose-1 150*4.6mm, Sum; mobile phase:
ethanol/hexane=15:85 (v/v);
1H NMR (400 mHz, CD30D): 7.90 (d, 8.0Hz, 2 H), 7.67(d, 8.0 Hz, 2 H), 7.62 (s, 0.5 H), 7.49 (s, 0.5 H), 4.59 (t, 8.0 Hz, 1 H), 4.38 (dd, 8.0, 11.0 Hz, 1 H), 4.27-4.11 (m, 1 H), 3.44-3.28 (m, 4 H), 3.20 (q, 8.0 Hz, 2 H), 2.24-2.01(m, 4H), 1.21 (t, 8.0 Hz, 3 H).
Example 127 Preparation of 5,7-dichloro-2-(4-((cyclopropylmethyl)sulfonyl)benzy1)-6-(4,4-difluoropiperidin-l-y1)-1H-benzo [di imid azo le CI
0.9 N N 's F __________________________________ I
CI N

Step 1: Preparation of cyclopropylmethyl 2-(4-(cyclopropylmethylthio) phenyl)acetate HO
To a solution of 2-(4-mercaptophenyl)acetic acid (5 g, 29.7 mmol) in DMF (50 mL), was added cesium carbonate (29.3 g, 89.1 mmol) and cyclopropylmethyl bromide (10 g, 74.21 mmol). The reaction mixture was stirred at room temperature overnight. It was distribute between water and ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and purified on a silica gel column, eluting with 25 % ethyl acetate in hexanes, to get cyclopropylmethyl 2-(4-(cyclopropylmethylthio)phenyl)acetate (7.7 g, 93.7 % yield) as a colorless oil. MS (+) ES: 277 (M+H) .
S tep2 : Preparation of cyclopropylmethyl 2- (4- (cyc loprop ylmethylsu lfonyl)phenyl) acetate s 0 0 [101 S

To a solution of cyclopropylmethyl 2-(4-(cyclopropylmethylthio)phenyl)acetate (4.07 g, 14.7 mmol) in dichloromethane (20 mL), was added MCPBA (7.61 g, 44.3 mmol) at room temperature. After addition, the reaction mixture was stirred at ambient temperature for 14 hours. It was distributed between dichloromethane and saturated sodium thiosulfate. The organic layer was washed with 2N aqueous sodium hydroxide solution and brine.
It was concentrated and purified on a silica gel column, eluting with 60 % ethyl acetate in hexanes, to get cyclopropylmethyl 2-(4-(cyclopropylmethylsulfonyl)phenyl)acetate (4.23 g, 93.0 %
yield) as a white solid. MS (+) ES: 309(M+H) .
5tep3: Preparation of 2-(4-(cyclopropylmethyl)sufonyl)phenyllacetic acid %S* 0 %S*

HO
To a solution of cyclopropylmethyl 2-(4-(cyclopropylmethylsulfonyl)phenyl)acetate (2.50 g, 8.1 mmol) in dioxane (10 mL), was added lithium hydroxide nomohydrate (4.1 g, 40.6 mmol) and water (10 mL). The reaction mixture was stirred at ambient temperature overnight. It was acidified with hydrochloric acid to pH 5, and concentrated to dryness. The solid collected was dissolved in 15% methanol in dichloromethane, and filtered through a silica gel pad, eluting with 15 % methanol in dichloromethane, and concentrated to get 2-(4-(cyclopropylmethyl)sufonyl)phenyllacetic acid (2.1 g, 97% yield) as a white solid. MS (+) ES: 255 (M+H) .
5tep4: Preparation of N- (6- amino -2,4-dichloro -3 -(4 ,4-difluoropiperidin-1 - yflpheny1)-2 - (4-(c yc loprop ylmethylsu lfonyephenyl) acetamide and N-(2 - amino-3 ,5 -dichloro-4 -(4,4-difluorop iperidin- 1 - yflpheny1)-2- (4- (cycloprop ylmethylsulfo nyl)phenyl) acetamide CI N H CI
0 1.1 0 FJJJCI 2 o * F...C.11 HO CI
and To a solution of 3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)benzene-1,2-diamine (175 mg, 0.193 mmol) and 2-(4-(cyclopentylmethyl sufonyl)phenyl)acetic acid (181 mg 0.711 mmol) in dichloromethane (5 mL) was added EDCI (171 mg, 0.89 mmol) and HBTU (334 mg, 0.89 5 mmol). The reaction solution was stirred at room temperature for 2 hours.
It was absorbed onto 5 g of silica gel, and loaded onto a silica gel column. The column was eluted with 45 %
of ethyl acetate in hexanes to get a mixture of N-(2-amino-3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)pheny1)-2-(4-(cyclopropylmethylsulfonyl)phenyl)acetamide and N-(6-amino -2,4 -dichloro -3 -(4 ,4-diflu oropiperidin- 1 - yl)pheny1)-2 -(4-10 (cyclopropylmethylsulfonyl)phenyl)acetamide (230 mg, 73.2 % yield) as a white solid. MS
(+) ES: 532 (M+H)+).
Step5: Preparation of 2-(4-(cyclopropylmethylsulfonyebenzy1)-4,6-dichloro-5-(4,4-difluoropiperidin- 1 - y1)- 1H-benzo [di imid azo le CI N H2 0 0 C I N CI O.
*k.0 CI NH 1.1 F-sk) CI N H2 CfS6 V F)ON F N

CI H
and F
The mixture of N- (2- amino -3 ,5 -dichloro -4- (4,4 -difluoropiperidin- 1 -yl)pheny1)-2 - (4-(c yc loprop ylmethylsu lfonyephenyl) acetamide and N-(6-amino-2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)pheny1)-2-(4-(cyclopropylmethylsulfonyl)phenyl)acetamide (230 mg) obtained from the previous step was treated with 15 mL of glacial acetic acid at 80 C for 2 hours. It was concentrated, and purified on a reverse phase column, eluting with 60 %
acetonitrile in water, to get 2-(4-(cyclopropylmethylsulfonyl)benzy1)-4,6-dichloro-5-(4,4-difluoropiperidin-l-y1)-1H-benzo [di imidazole (375 mg, 94.8 % yield) as a pale solid; MS (+) ES: 514 (M+H)+;
1 H NMR (500 mHz, CDC13): 7.85 (d, 5.00 Hz, 2 H), 7.66 (s, 0.5 H), 7.50 (d, 5.00 Hz, 2 H), 7.30 (s, 0.5 H), 4.45 (m, 2 H), 3.30 (m, 4 H), 3.00 (m, 2 H), 2.12 (m, 5 H), 0.51 (m, 2 H), 0.35 (m, 2 H).
Example 128 Preparation of 2-(7 -chloro-6 - (2- (difluorometho xy)pheny1)- 1H-b enzo [di imidazol-2- y1)-2 -(4-((cyclopropylmethyl)sulfonyl)phenyl)ethanamine oõp F)c) CI

Step 1. Preparation of benzyl 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)acetate 0 w 9 9 o 0 0 v To a suspended CH2C12 (10 ml) solution of 2-bromo-1-methylpyridinium iodide (2.16 g, 7.2 mmol) was added a mixture of benzyl alcohol (648 mg, 6.0 mmol), 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)acetic acid (1.5 g, 6.0 mmol) and tri-n-butylamine (2.66 g, 14.4 mmol) in CH2C12 (8 ml), and the resulting mixture was refluxed for 3 hours. After evaporation of the solvent, the residue was separated by silica gel column chromatography, and benzyl the product was isolated as a white solid 1.8 g (90% yield). MS (+) ES: 344 (M+H) .
Step 2. Preparation of benzyl 2-(4-((cyclopropylmethyl)sulfonyflpheny1)-3-(1,3-dioxoisoindolin-2- yl)prop ano ate 0 Br 0 0 A solution of n-butyllithium in THF (1.8 ml, 2.5 M, 4.5mm01) was added in to a cooled mixture of HMDS (608 mg, 4.56 mmol) in THF (20 ml) dropwise over 20 mm with stirring.
The mixture was stirred for 30 mm before benzyl 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)acetate (1.3 g, 3.8 mmol) in THF (5 ml) was added through a syringe dropwise over 10 min. Stirred for another 30 mm at -78 C
followed by the addition of 2-(bromomethyl)isoindoline-1,3-dione (912 mg, 3.8 mmol) in THF (5 ml) was added through a syringe over 10 mm. The mixture was stirred at -78 C and allowed to reach to room temperature overnight. The mixture was treated with methanol carefully and the solvents were evaporated. The product was purified by flash chromatography to affod the product as a White solid 1.4 g (74% yield). MS (+) ES: 504 (M+H) .

Step 3. Preparation of 2 -(4- ((c ycloprop ylmethyl) s ulfo nyl)pheny1)-3 -(1,3 -dio xo isoindo lin-2-yl)propanoic acid Benzyl 2-(4 - ((cyc loprop ylmethyl)sulfonyl)pheny1)-3 -(1,3 -dioxoisoindolin-2- yl) propanoate in step 2 (1.4 g, 2.8 mmol) was dissolved in ethyl acetate (20 mL) and Pd(OH)2 (140 mg) was added and the mixture was hydrogenated with a hydrogen balloon for 8 h.
Catalyst was filtered off and the solvent was evaporated to leave a White solid product 900 mg (78% yield). MS (+) ES: 414 (M+H) .
Step 4. Preparation of 6-chloro-2'-(difluoromethoxy)-11,1'-bipheny11-3,4-diamine CI NH2 Pd (dba) t-Bu P-BF
2 3, 3 4) Br NH2 Na2003, dioxane/H20 F
A mixture of 4-bromo-5-chlorobenzene-1,2-diamine (1.5 g, 6.78 mmol), 2-(2-(difluorometho xy)pheny1)-4 ,4 ,5 ,5 -tetramethyl- 1,3 ,2 -dio xaboro lane (2.2 g, 8.15 mmol), tris-(dibenzylideneacetone)dipalladium(0) (620 mg), tri(tert-butyl) phosphonium tetrafluoroboronate (393 mg) and sodium carbonate (1.7 g, 13.7 mmol) in 1,4-dioxane (50 ml) and water (10 mL) was degassed, heated to 90 C under for 3h. The volatile solvents were removed under reduced pressure. The residue was directly loaded onto a ISCO solid cartridge and flashed with hexane/ethyl acetate to afford the product 1.0 g (51.9% yield), MS
(+) ES: 285 (M+H) .
Step 5. Preparation of 2-(2-(5-chloro-6-(2-(difluoromethoxy)pheny0-1H-benzo [di imidazol-2- yl) -2- (4-((c yc loprop ylmethyl) su lfo nyl)phenyl)ethyl)isoindo line- 1 ,3-dione 0*
0 *

NH
0 c, HO

0 0)_F

To a mixture of 2- (4-((c ycloprop ylmethyl) sulfo nyl)pheny1)-3 - (1 ,3 -dio xo isoindo lin-2-yl)propanoic acid (step3, 400 mg, 0.97 mmol) and 6-chloro-2'-(difluoromethoxy)41,1'-bipheny11-3,4-diamine (step 4; 275 mg, 0.98 mmol) in DMF (8 ml) was added N-(3-Dimethylaminopropy1)-N-ethylcarbodiimide hydrochloride 224 mg, 1.2 mmol) and 1-Hydroxybenzotriazole (162 mg, 1.2 mmol). The mixture was stirred at room temperature overnight, partitioned between ethyl acetate (10 ml) and water (15 m1). The organic phase was separated and dried over MgSO4. After filtration and evaporation of the solvent the residue was treated with acetic acid (5 ml) and heated to 80 C for two hours.
The mixture was cooled and the acetic acid was evaporated to dryness, dissolved in ethyl acetate (10 ml) washed with saturated sodium bicarbonate and brine. The organic phase was separated and dried over MgSO4. The product was purified by flash chromatography to afford a white solid 454 mg (70% yield). MS (+) ES: 662 (M+H) .
Step 6. Preparation of 2-(5 -chloro-6- (2- (difluorometho xy)pheny1)- 1H-benzo ldlimidazol-2-y1)-2-(4-((cycloprop ylmethyl)sulfonyl)phenyl)ethanamine 0 N AU, CI NH

)¨F
24245 -chloro -6- (2 -(difluorometho xy)pheny1)- 1H-benzo [di imid azol-2- y1)-2-(4 -((cyclopropylmethyl)sulfonyl)phenyl)ethyl)isoindoline-1,3-dione (step 4, 454 mg, 0.68 mmol) was dissolved in ethanol (5 m1). hydrazine hydrate (0.1 mL) was added and the mixture was stirred overnight. The solid precipitate was filtered off and the volatile solvents was evaporated to dryness. The product was purified by flash chromatography to afford the product as a white solid 280 mg (76% yield). MS (+) ES: 532 (M+H) .
Example 129 Preparation of N-(2-(5-chloro-6-(2-(difluoromethoxy)pheny0-1H-benzo [di imidazol-2-y1)-2-(4-((cyclopropylmethyl)sulfonyl)phenyl)ethyl)acetamide o NH

N NH 41111..-ib rV

)¨F 129 NH

CI NH RIP

)-F F

)-F
To a solution of 2-(5-chloro-6-(2-(difluoromethoxy)pheny1)-1H-benzoldlimidazol-2-y1)-2-(4-((cyclopropylmethyl)sulfonyl)phenyllethanamine(example 128) (5.3 mg, 0.01 mmol) and triethyl amine (3 mg, 0.03 mmol) in DCM (0.4 mL) was added acetic anhydride (1.2 mg, .. 0.012 mmol). The mixture was stirred for 4h. Solvent was evaporated under reduced pressure and the product was purified by Prep HPLC to afford the product as a white solid 3.5 mg (66% yield). MS (+) ES: 574 (M+H) Example 130 Preparation of 3 - (4,6-dichloro-5 - (4,4 -difluorop iperidin- 1 - y1)- 1H-benzo [di imid azol-2- y1)-3 -(4-(ethylsulfonyl)phenyl)propanoic acid CI
F? _________________________________ *
NH
O
CI H

Step 1: Preparation of 4-ethoxy-2-(4-(ethylsulfonyl)pheny1)-4-oxobutanoic acid HO Li HMOS
0 io Br HO
OCl2Et 002E1 To 2-(4-(ethylsulfonyl)phenyl)acetic acid (250 mg, 1.1mmol) in THF (8mL) at -78 C was added LiHMDS(1M in THF, 2.31mL). After 50min, ethyl 2-bromoacetate (147 iaL, 1.32mmo1) was added. The reaction mixture was stirred at -78 C for 3.5h. 0.1N
HC1 solution was added to adjust pH to around 4. Extracted with Et0Ac three times, dried over Na2SO4, filtered, concentrated. The residue was purified by silica gel column with elution system A to give yellow oil 29 mg. MS (ESI): 315 (M+H) .
Step 2: Preparation of ethyl 4-((2-amino-3,5-dichloro-4-(4,4-difluoropiperidin-yl)phenyl) amino)-3 -(4- (ethylsulfonyl)pheny1)-4 -oxobutano ate F'F. CI

F F

HO)CQ NH2 I 0 CI NYQ
CO2Et HATU NH2 CO2Et To a solution of 4-ethoxy-2-(4-(ethylsulfonyl)pheny1)-4-oxobutanoic acid (27 mg) in DCM (1 mL) , 3,5 -dichloro-4- (4,4-diflu oropiperidin- 1 - yl)benzene- 1 ,2-diamine(65 mg), HATU (150mg), DIEA (0.1mL) were added. The mixture was stirred at room temperature for 18h. A solution of saturated NaHCO3 was added, extracted Et0Ac three times, dried over Na2SO4, filtered, concentrated. The residue was purified by silica gel column with elution system A to obtain the title compound 40 mg. MS (ESI): 593 (M+H) Step 3: Preparation of ethyl 3 -(4 ,6-dichloro-5 - (4,4-diflu orop ip eridin- 1 - y1)- 1H-benzo [di imid azol-2- y1)-3 - (4- (ethylsulfonyl)phenyeprop ano ate oo 0 AcOH 0 N NH

CI
H CI OP
CO2Et 7¨r\ CI
10 F \
Ethyl 4- ((2 - amino-3 ,5 -dichloro-4 -(4 ,4-diflu orop ip eridin- 1 - yl)phenyl)amino)-3 -(4-(ethylsulfonyl) phenyl)-4-oxobutanoate (39 mg) in AcOH (2mL) was heated to 80 C for 3h.
The mixture was purified by silica gel column with elution system C to give the title compound (18 mg). MS (ESI): 574 (M+H) .
15 Step 4: Preparation of 3 - (4 ,6-dichloro -5- (4 ,4 -diflu oropiperidin-1 - y1)- 1H-benzo [d]imidazol-2-y1)-3-(4-(ethylsulfonyl)phenyl)propanoic acid Li OH/THF/Me0H HO s*
N NH N NH
CI 0' CI 0' /-1\1 CI 7-1\I CI
F \ F \
Ethyl 3- (4 ,6-dichloro-5 - (4,4-diflu orop ip eridin- 1 - y1)- 1H-b enzo [di imidazol-2- y1)-3 -(4-(ethylsulfonyl)phenyl)propanoate (18 mg) in THF (1.5mL)/Me0H(0.5mL) was treated with Li0H(1M, 0.2mL). The mixture was stirred at room temperature for 3h until no ethyl 3-(4,6-dichloro-5-(4,4-difluoropiperidin- 1 - y1)- 1H-benzo [di imid azol-2- y1)-3 -(4 -(ethylsulfonyl)phenyl) propanoate left by LCMS. 1M HC1 was added to adjust pH
<5.
Solvent was evaporated under reduced pressure and the product was purified by reverse phase prepative HPLC (elution system: 0.075% TFA in water and 0.075% TFA in Me0H) to afford the title compounds as a white solid (11 mg). MS (ESI): m/z = 546 (M+H) .
Example 131 Preparation of 3 -(4,6 -dichloro -5- (4 ,4-difluoropiperidin- 1 - y1)- 1H-benzo [di imid azol-2- y1)-3 -(4-(ethylsulfonyl)phenyl)propanamide a o \N N
F7\ W I
CI N

NI' NH
CI =
CI =
F \
r) CI
rN) CI
F \
To a solution Example 172 (9 mg) in DMF (1mL) were added NH4C1 (30 mg), HATU
(17 mg), DIEA (60 L). The mixture was stirred a room temperature for 20h. The solid was filtered off. The filtrate was purified by reverse phase prepative HPLC
(elution system:
0.075% TFA in water and 0.075% TFA in Me0H) to afford the title compounds as a white solid (3mg). MS (ESI): m/z = 545 (M+H) Examples 132 Preparation of 5,7-dichloro-2-(4-((cyclopropylmethyl)sulfonyl)benzy1)-6-(2-isopropoxyphenyl)-1H-benzo [di imid azole 0, 0 -s*
ci N
CI

This compound was prepared by essential the similar method as of example 124 to afford the product as a white solid, MS (+) ES: 529 (M+H) .
Examples 133 Preparation of (4-((cyclopropylmethyl)sulfonyl)phenyl)(5,7-dichloro-6-(2-isopropoxyphenyl)-1H-benzo [di imidazol-2-yl)methanol = CI
N OH
CI

This compound was prepared by essential the similar method as of example 2 and 124 to afford the product as a white solid, MS (+) ES: 545 (M+H) .
Examples 134 Preparation of 2-(4-((cyclopropylmethypsulfonyl)phenyl)-2-(5,7-dichloro-6-(2-isopropoxypheny1)-1H-benzo [di imidazol-2-yDethanol o o CI
CI HO

This compound was prepared by essential the similar method as of example 124 to afford the product as a white solid, MS (+) ES: 559 (M+H) .
Examples 135 Preparation of 2-(4-((cyclopropylmethypsulfonyl)phenyl)-2-(5,7-dichloro-6-(2-methoxypheny1)-1H-benzo [di imidazol-2-yDethanol o o CI
CI HO

This compound was prepared by essential the similar method as of example 124 to afford the product as a white solid, MS (+) ES: 531 (M+H) .

Examples 136 Preparation of 5,7-dichloro-2-(4-((cyclopropylmethyl)sulfonyl)benzy1)-6-(2-ethoxyphenyl)-1H-benzoldlimidazole c\I\g CI
CI

This compound was prepared by essential the similar method as of example 124 to afford the product as a white solid, MS (+) ES: 515 (M+H) .
Examples 137 Preparation of 2-(4-((cyclopropylmethypsulfonyl)phenyl)-2-(5,7-dichloro-6-(2-ethoxypheny1)-1H-benzokllimidazol-2-yDethanol o , CI HO

This compound was prepared by essential the similar method as of example 124 to afford the product as a white solid, MS (+) ES: 545 (M+H) .
Examples 138 Preparation of (4-((cyclopropylmethyl)sulfonyl)phenyl)(5,7-dichloro-6-(2-ethoxypheny1)-1H-benzokllimidazol-2-y1)methanol o o CI
N OH
CI

This compound was prepared by essential the similar method as of example 2 and 124 to .. afford the product as a white solid, MS (+) ES: 531 (M+H) .

Examples 139 and 140 Preparation of (S)-3-(4,6-dichloro-5-(4,4-difluoropiperidin-l-y1)-1H-benzo [di imidazol-2-y1)-3-(4-(ethylsulfonyflphenyl)propan-l-ol and (R)-3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-y1)-1H-benzo [di imidazol-2-y1)-3-(4-(ethylsulfonyl)phenyl) propan-l-ol Eto2s EtO2S F
F
F
li CI aF le CI
Nr N/ 40 N......-1\I I.

N CI N CI
H H
HO HO

Et0 CH2Cl2 Et0 1. KOH/Me0H HO
_,.. ___________________________________________________ ....
0 K2003/DMF 0 MCPBA 0 1101 2. HCI 0 SH SEt SO2Et SO2Et LiHMDS/THF

Et0 Br Et0 0 SO2Et NCS 02N .0 CI
DIPEA 02N al CI
Fe, NH4CI .. H2N di. CI
_õ,.
DMF
H2N CI H2N CI DMF H2N 1111" N Me0H/H20 CI CI F CI 1.õ.õ..F
F F
F

+

EDCl/HOBt/ DMF F
Et0 a r.LF EtO2S 82N 40 N..........-________________________ = N + 401 N,.......-CI
N H
Et0 0 SO2Et EtO2S q2N CI Et0 EtO2S EtO2S
F F
CI 1------i¨F L1AIH4 CI
/
HOAc _õ..
ref lux /I \ I 0 NI -../ THF N N., N CI N CI
H H

Et0 HO
EtO2S EtO2S
F F
Chiral seperation * 41/ CI .LF F
/1\I 0 N -,.---- CI
N N, /

H H
HO HO
Step 1. Preparation of ethyl 2-(4-(ethylthio)phenyl)acetate HO Et0 /1 ..

SH SEt To a solution of (4-mercaptophenyl) acetic acid (5.0 g, 29.7 mmol) in N,N-dimethylformamide (DMF) (100 ml) was added K2CO3 (16.4 g, 118.8 mmol) and Iodoethane (9.7 g, 62.2 mmol). The reaction mixture was stirred at RT. After 12 hours, the starting material was totally consumed. The reaction mixture was partitioned between ethyl acetate (100 ml) and water (50 ml). The organic phase was washed with water (30 ml) and brine (20 ml), dried over sodium sulphate, filtered, and concentrated to give the desired product ethyl 2-(4-(ethylthio)phenyl)acetate (6.0 g, 90%) as a pale yellow solid, MS (+) ES:
225(M+H) Step 2. Preparation of ethyl 2-(4-(ethylsulfonyl)phenyl)acetate Et0 CH2Cl2 Et0 SEt SO2Et To a 250 ml round bottom flask, were added ethyl 2-(4-(ethylthio)phenyl)acetate (6.0 g, 26.7 mmol) and dichloromethane (300 ml). The reaction mixture was cooled to 0 C. To the same flask, m-chloroperbenzoic acid (13.8 g, 80.0 mmol) was added at 0 C. The reaction mixture was stirred at room temperature for 12 h. The resulting suspension was filtered through a pad of celite. The filtrate was washed with water. The organic layer was separated, washed with saturated sodium bicarbonate solution followed by brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by flash column chromatography with hexane/ethyl acetate to get the title compound as an oil that was solidified upon standing (6.0 g, 87.5%), MS (+) ES: 257 (M+H) .
Step 3. Preparation of 2-(4-(ethylsulfonyl)phenyl)acetic acid Et0 0 1101 1 KOH/Me0H HO
2 HCI 0 1.1 SO2Et SO2Et To a 250 mL round bottom flask, were added ethyl 2-(4-(ethylsulfonyl)phenyl)acetate (6.8 g, 26.5 mmol) and methanol (80 ml). To the same flask, a solution of sodium hydroxide in water (2.1 g, 52.5 mmol in 20 ml of water) was added. The reaction mixture was heated to reflux for 12 h. The volatiles were evaporated under reduced pressure. The residue was acidified with 1N HC1 to pH 5.0 and extracted with ethyl acetate (50 m1x3).
The organic layer was separated and combined, washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to get the title compound as a white solid (3.3 g, 54.5%), MS (+) ES: 229 (M+H) .

Step 4. Preparation of 4-ethoxy-2-(4-(ethylsulfonyl)pheny1)-4-oxobutanoic acid LIHMDS/THF
HO _______________________________________ a.

0 SO2Et Et0 Br Et0 0 SO2Et To 2-(4-(ethylsulfonyl)phenyl)acetic acid (1.0 g, 4.4mm01) in THF (20mL) at -78 C was added LiHMDS(1M in THF, 9.0 mL). After 15min, ethyl 2-bromoacetate (1.1 g, 6.58 mmol) was added. The reaction mixture was stirred at -78oC for 3.5h. 0.1N HC1 solution was added to adjust pH to around 4. Extracted with Et0Ac three times, dried over Na2SO4, filtered, concentrated. The residue was purified by silica gel column with elution system A to give yellow oil 0.45 g. MS (ESI): 315 (M+H) Step5. Preparation of 2,3,4-Trichloro-6-nitrobenzenamine 02N c, NCS 02N is CI
DMF

CI
A suspension of 4,5-dichloro-2-nitrobenzenamine (10 g, 48.3 mmol) and N-chlorosuccinimide (7.7 g, 57.6 mmol) in 100 mL of DMF was stirred at 100 C for 2 hours. It was cooled to room temperature, and poured into ice-cooled water (500 mL). The precipitate formed was collected by filtration. It was dissolved in dichloromethane and washed with water. The organic layer was concentrated to get 2,3,4-trichloro-6-nitrobenzenamine (11.0 g, 94.3 % yield) as a brightly yellow solid.
Step 6. Preparation of 2 ,4-Dichloro-3-(4 ,4-difluoropiperidin-l-y0-6-nitrobenzenamine DIPEA 02N i& Cl CI CI .\-F
A solution of 2,3,4-trichloro-6-nitrobenzenamine (5 g, 20.7 mmol), N,N-diisopropyl ethylamine (8.0 g, 61.9 mmol), and 4,4-difluoropiperidine (10.0 g, 157.6 mmol) in 50 mL of DMF was stirred at 105 C for 2 days. The reaction solution was absorbed onto 40 g of silica gel, loaded to a silica gel column, and eluted with 30% ethyl acetate in hexanes, to get the 2,4-dichloro-3-(4,4-difluoropiperidin-1-y0-6-nitrobenzenamine (2.0 g, 29.6 %
yield) as a brightly yellow solid. MS (ESI): 326 (M+H) Step 7. Preparation of 3,5 -Dichloro-4-(4,4 -difluoropiperidin-1 - yl)b enzene-1,2 -diamine 02N i& CI H2N i& CI
Fe, NH4CI
H2N N Me0H/H20 H2N N
CI F CI
To a solution of 2,4-dichloro-3-(4,4-difluoropiperidin-1-y1)-6-nitrobenzenamine (2.0 g, 6.1 mmol) in 120 mL of methanol and 30 mL of water was added Fe powder (1.0 g, 18.0 mmol) and NH4C1 (1.0 g, 18.5 mmol). The reaction mixture was stirred at 80 oC
overnight.
It was filtered. The filtrate was concentrated, and purified on a silica gel column, eluting with ethyl acetate, to get 3,5-dichloro-4-(4,4-difluoropiperidin-1-y1) benzene-1,2-diamine (0.6 g, 33.0 % yield) as a pale solid (LCMS (M+1): 296).
Step 8. Preparation of ethyl 4-((2-amino-3,5-dichloro-4-(4,4-difluoropiperidin-yl)phenyl)amino)-3-(4-(ethylsulfonyl)pheny1)-4-oxobutanoate and ethyl 4-((6-amino-2,4-dichloro-3 - (4,4 -difluorop iperidin- 1 - yl)phenyl) amino)-3 - (4-(ethylsulfo nyl)pheny1)-4-oxobutanoate H2N N EDCl/HOBt/ DMF
CI Et0 0 SO2Et CI
EtO2S 82N fah Et0 CI ri-F

N CI
Et0 EtO2S 92N CI
To a solution of 3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)benzene-1,2-diamine (450 mg, 1.43 mmol) and 4-ethoxy-2-(4-(ethylsulfonyl)pheny1)-4-oxobutanoic acid (424 mg, 1.43 mmol) in DMF (10 mL) was added EDCI (410 mg, 2.15 mmol), HOBT (327 mg, 2.15 mmol) and DIPEA(554 mg, 4.30 mmol). The reaction solution was stirred at room temperature for 2 hours. It was absorbed onto 5 g of silica gel, and loaded onto a silica gel column. The column was eluted with 45 % of ethyl acetate in hexanes to get a mixture of ethyl 4-((2 - amino-3 ,5 -dichloro-4 -(4,4-diflu oropip eridin- 1 - yl)phenyl)amino)-3 -(4-(ethylsulfonyl)pheny1)-4-oxobutanoate and ethyl 4-((6-amino-2,4-dichloro-3-(4,4-difluorop iperidin- 1 - yl)phenyl)amino)-3 -(4- (ethyls ulfonyl)pheny1)-4 -oxobutano ate (385 mg, 45.4 % yield) as a white solid. MS (ESI): m/z = 592 (M+H) .

Step 9. Preparation of ethyl 3 - (4,6-dichloro-5 - (4,4 -difluorop iperidin-1 -y1)-1H-benzo [di imid azol-2- y1)-3 - (4- (ethylsulfonyl)phenyeprop ano ate H nith Et0 CI r.. EtO2S 2N -'`..LF 0 HOAc N N CI ref lux EtO2S (2N CI Et0 EtO2S
CI
N
N 1111" ci OH
Et0 The mixture of ethyl 4-((6- amino-2 ,4-dichloro-3 -(4,4-difluorop ip eridin- 1 -yl)phenyl) amino)-3 -(4- (ethylsulfonyl)pheny1)-4 -oxobutano ate andethyl 4 -((2- amino -3 ,5 -dichloro-4- (4,4 -difluorop iperidin- 1 - yl)phenyl) amino)-3 - (4-(ethylsulfo nyl)pheny1)-4-oxobutanoate (385 mg) obtained from the previous step was treated with 15 mL
of glacial acetic acid at 80 C for 2 hours. It was concentrated, and purified on a silica gel column, eluting with 60 % ethyl acetate in hexanes, to get ethyl 3-(4,6-dichloro-5-(4,4-difluorop iperidin- 1 - y1)- 1H-benzo [di imid azol-2- y1)-3 - (4-(ethylsu lfonyl)phenyl)prop ano ate (230 mg, 61.6% yield) as a pale solid. MS (ESI): 574 (M+H) Step 10. Preparation of (S)-3 -(4,6-dichloro-5 - (4,4 -difluorop iperidin- 1 -y1)- 1H-benzo [di imid azol-2- y1)-3 - (4- (ethylsulfonyl)phenyeprop an- 1 -ol and (R)-3 - (4,6-dichloro-5 -(4,4-diflu oropip eridin- 1 - y1)- 1H-b enzo [di imidazol-2 - y1)-3 - (4-(ethylsu lfonyephenyl) prop an-1 -ol EtO2S EtO2S
Cl ri¨F CI
LiAIH4 N N N
THF
N 11}1 ci N 11}1 OH
Et0 HO
EtO2S EtO2S
CI r¨F CI
N
Chiral seperation N 411"1 ci ' N CI
) H
HO HO
To a solution of ethyl 3 -(4 ,6-dichloro-5 - (4,4-difluorop ip eridin- 1 - y1)- 1H-benzo ldlimidazol-2-y1)-3-(4-(ethylsulfonyl)phenyepropanoate (300 mg, 0.52 mmol) in THF
(20 ml) was added LiA1H4 (20 mg, 0.52 mmol)at 0 C. The reaction mixture was stirred at room temperature for 1 h. 5.0 mL water was added, the mixture was filtered.
The filtrate was concentrated, the crude product was purified by flash column chromatography with hexane/ethyl acetate to get 3-(4 ,6-dichloro-5 -(4,4-diflu orop ip eridin- 1 - y1)- 1H-benzo [di imid azol-2- y1)-3 -(4-(ethylsulfonyl)phenyeprop an- 1 -ol (200 mg).
It was separated chirally (separation conditions: CHIRALCEL OZ-H(OZHOOCD-VC005), 0.46 cm I.D. x 15 cm L; mobile phase :
Hexane/Et0H/DEA=70/30/0.1(V/V/V);
flow rate: 1.0 mL/min), The corresponding fractions were collected and concentrated under reduced pressure to obtain the title compounds (85 mg, 89 mg).
Single configuration compound (the shorter retention time) MS (+) ES: 532 (M+H)+;
Chiral HPLC analysis: retention time 7.640 minutes, chiral purity: 100%
(chromatographic column: OD Phenomenex Lux Cellulose-1 150*4.6mm,5um; mobile phase:
ethanol/hexane=15:85 (v/v);
1H NMR (400 mHz, CD3C1): 7.90 (d, 8.0 Hz, 2H), 7.72 (s, 1H), 7.68 (d, 8.0 Hz, 2H), 4.68 (t, 8.0 Hz, 1H), 3.76 (t, 8.0 Hz, 2H), 3.71(m, 4H), 3.14-3.12 (m, 2H), 2.65-2.60 (m, 1H), 2.38-2.35 (m, 1H), 2.10-2.10 (m, 4H), 1.23-1.19 (t, 8.0 Hz, 3 H).
Single configuration compound (the longer retention time) MS (+) ES: 532 (M+H) .
Chiral HPLC analysis: retention time 9.398 minutes, chiral purity: 100%
(chromatographic column: OD Phenomenex Lux Cellulose-1 150*4.6mm,5um; mobile phase:
ethanol/hexane=15:85 (v/v);
1H NMR (400 mHz, CD30D): 7.90 (d, 8.0 Hz, 2H), 7.72 (s, 1H), 7.68 (d, 8.0 Hz, 2H), 4.68 (t, 8.0 Hz, 1H), 3.76 (t, 8.0 Hz, 2H), 3.71(m, 4H), 3.14-3.12 (m, 2H), 2.65-2.60 (m, 1H), 2.38-2.35 (m, 1H), 2.10-2.10 (m, 4H), 1.23-1.19 (t, 8.0 Hz, 3 H).
Example 141 Preparation of 3 -(5 -chloro-6-(2-(diflu oro methoxy)pheny1)- 1H-benzo [di imidazol-2 - y1)-3 -(4-((c yc loprop ylmethyl)sulfonyl)phenyl)prop anamide CI
\ 0 F

This compound was prepared by the same method as of racemic mixture of Examples 152 and 153. MS (+) ES: 560 (M+H) .
Example 142 Preparation of 3-(5-chloro-6-(2-(difluoromethoxy)pheny1)-1H-benzo [di imidazol-2-y1)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propan-l-ol CIGH N
OH

F)F

This compound was prepared by the same method as of racemic mixture of Examples 155 and 156. MS (+) ES: 547 (M+H) .
Example 143 Preparation of 3-(5-chloro-6-(2-isopropoxypheny1)-1H-benzo [di imidazol-2-y1)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanamide \\e-\
CI

This compound was prepared by the same method as of racemic mixture of Examples 148 and 149. MS (+) ES: 552 (M+H) .
Example 144 Preparation of 3-(5-chloro-6-(2-isopropoxypheny1)-1H-benzo [di imidazol-2-y1)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propan-l-ol oµp \s'¨\
I
CI
OH

This compound was prepared by the same method as of racemic mixture of Examples 150 and 151. MS (+) ES: 539 (M+H) .
Example 145 Preparation of 3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-y1)-1H-benzo [di imidazol-2-y1)-3-(4-(ethylsulfonyl)phenyl)propan-l-ol \\e¨\
CI
N
CI
OH

This compound was prepared by the same method as of racemic mixture of example 139 and 140. MS (+) ES: 532 (M+H) .
Examples 146 and 147 Preparation of (S)-3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-y1)-1H-benzo [di imidazol-2-y1)-3-(4-(ethylsulfonyflphenyl)propanamide and (R)-3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-y1)-1H-benzo [di imidazol-2-y1)-3-(4-(ethylsulfonyl)phenyl)propanamide Eto2s EtO2S
CI r'sl¨F
CI OLF
N
N N CI
OH
OH

EtO2S EtO2S
CI ri¨F CI ri¨F
i& r\l/ NH3 i& r\l/ Chiral seperation.
Me0H
N CI N CI
OH OH
Et0 H2N
EtO2S EtO2S
CI ri¨F CI ri¨F
N CI N CI
OH

To a solution of ethyl 3 -(4 ,6-dichloro-5 -(4,4-diflu orop ip eridin-1 - y1)-1H-benzo [di imidazol-2-y1)-3-(4-(ethylsulfonyl)phenyepropanoate (310 mg, 0.54 mmol) in methanol(20 ml) was added NH3 (7.7 mL, 7N inmethanol, 53.9 mmol). The reaction mixture was stirred at 60 C for 12 h. the mixture was concentrated, the crude product was purified by flash column chromatography with hexane/ethyl acetate to get 3-(4,6-dichloro-5-(4,4-difluoropiperidin- 1 - y1)- 1H-benzo [di imid azol-2- y1)-3 -(4-(ethylsu lfonyl)phenyl)prop anamide (300 mg).
It was separated chirally (separation conditions: CHIRALCEL OZ-H(OZHOOCD-VC005), 0.46 cm I.D. x 15 cm L; mobile phase: 100% methanol; flow rate: 1.0 mL/min), The corresponding fractions were collected and concentrated under reduced pressure to obtain the title compounds (140 mg, 135 mg).
Single configuration compound (the shorter retention time) MS (+) ES: 545 (M+H)+;
Chiral HPLC analysis: retention time 9.537 minutes, chiral purity: 100%
(chromatographic column: OD Phenomenex Lux Cellulose-1 150*4.6mm,5um; mobile phase:
ethanol/hexane=15:85 (v/v);
1H NMR (400 mHz, CD30D): 7.84 (d, 8.0 Hz, 2H), 7.63 (d, 8.0 Hz, 2H), 7.57 (s, 1H), 6.44 (s, 1H), 5.71 (s, 1H), 5.14 (t, 8.0Hz, 1H), 3.74-3.68 (dd, 8.0 Hz, 1H), 3.2-3.22 (m, 4H), 3.15-3.09 (q, 2H), 3.09-3.03 (dd, 8.0 Hz, 1H), 2.18-2.10 (m, 4H), 1.31-1.27 (t, 8.0Hz, 3 H).
Single configuration compound (the longer retention time) MS (+) ES: 545 (M+H)+;
Chiral HPLC analysis: retention time 11.851 minutes, chiral purity: 100%
(chromatographic column: OD Phenomenex Lux Cellulose-1 150*4.6mm,5um; mobile phase:
ethanol/hexane=15:85 (v/v);

1H NMR (400 mHz, CD30D): 7.84 (d, 8.0 Hz, 2H), 7.63 (d, 8.0 Hz, 2H), 7.57 (s, 1H), 6.44 (s, 1H), 5.71 (s, 1H), 5.14 (t, 8.0 Hz, 1H), 3.74-3.68 (dd, 8.0 Hz, 1H), 3.2-3.22 (m, 4H), 3.15-3.09 (q, 2H), 3.09-3.03 (dd, 8.0 Hz, 1H), 2.18-2.10 (m, 4H), 1.31-1.27 (t, 8.0Hz, 3 H).
Examples 148 and 149 Preparation of (S)-3 -(6 -chloro-5 -(2-isopropoxypheny1)-1H-benzo [di imid azol-2- y1)-3 -(4 -((cyclopropylmethyl)sulfonyl)phenyl)propanamide and (R)-3-(6-chloro-5-(2-isopropoxypheny1)-1H-benzo [di imid azol-2- y1)-3 -(4 -((c yc loprop ylmethyl) su lfonyl)phenyl)prop anamide ,s d 0 d N CI CI

lo 148 149 <c_e =<:. <Le =
NH3 (:5' Me0H IMF /NI
N CI N CI

Eta H2N

<c_d?

W N
N CI
>=0H

To a solution of ethyl 3-(6-chloro-5-(2-isopropoxypheny1)-1H-benzoldlimidazol -2-y1)-3-(4-((cyclopropylmethyl)sulfonyflphenyflpropanoate (340 mg, 0.59 mmol) in methanol(5 ml) was added NH3 (4.1 mL, 7N inmethanol, 29.2 mmol). The reaction mixture was stirred at 60 C for 12 h. the mixture was concentrated, the crude product was purified by flash column chromatography with hexane/ethyl acetate to get the title compound (220 mg).
It was separated chirally (separation conditions: CHIRALCEL OZ-H(OZHOOCD-VC005), 0.46 cm I.D. x 15 cm L; mobile phase : 100% methanol; flow rate: 1.0 mL/min), The corresponding fractions were collected and concentrated under reduced pressure to obtain 3 -(6-chloro-5-(2-isopropoxypheny1)-1H-benzo [di imidazol-2- y1)-3 -(4-((cyclopropylmethyl)sulfonyl)phenyl)propanamide (97 mg, 87mg).
Single configuration compound (the shorter retention time) MS (+) ES: 552 (M+H) Chiral HPLC analysis: retention time 5.617 minutes, chiral purity: 100%
(chromatographic column: OD Phenomenex Lux Cellulose-1 150*4.6mm,5um; mobile phase:
ethanol/hexane=70:30 (v/v);
1H NMR (400 mHz, CD30D): 7.92 (d, 8.0Hz, 2 H), 7.65 (d, 8.0 Hz, 2 H), 7.51-7.49 (s, 1H), 7.35-7.31 (t, 8.0Hz, 1H), 7.28(s, 1H), 7.16-7.14 (d, 8.0Hz, 1H), 7.05-7.03 (d, 8.0Hz, 1H), 7.00-6.96 (d, 8.0Hz, 1H), 4.95-4.91 (t, 8.0Hz, 1H), 4.51-4.46 (m, 1H), 3.39-3.34 (dd, 8.0Hz, 1H), 3.13-3.11(d, 8.0Hz, 2H), 3.12-3.06 (dd, 8.0Hz, 1H), 1.16-1.15(d, 4.0Hz, 6H), 0.93-0.91(m, 1H), 0.51-0.49(d, 8.0Hz, 2H), 0.13-0.11 (d, 8.0Hz, 2H).
Single configuration compound (the longer retention time) MS (+) ES: 552 (M+H) Chiral HPLC analysis: retention time 15.283 minutes, chiral purity: 100%
(chromatographic column: OD Phenomenex Lux Cellulose-1 150*4.6mm,5um; mobile phase:
ethanol/hexane=70:30 (v/v);
1H NMR (400 mHz, CD30D): 7.92 (d, 8.0Hz, 2 H), 7.65 (d, 8.0 Hz, 2 H), 7.51-7.49 (s, 1H), 7.35-7.31 (t, 8.0Hz, 1H), 7.28 (s, 1H), 7.16-7.14 (d, 8.0Hz, 1H), 7.05-7.03 (d, 8.0Hz, 1H), 7.00-6.96 (d, 8.0Hz, 1H), 4.95-4.91 (t, 8.0Hz, 1H), 4.51-4.46 (m, 1H), 3.39-3.34 (dd, 8.0Hz, 1H), 3.13-3.11(d, 8.0Hz, 2H), 3.12-3.06 (dd, 8.0Hz, 1H), 1.16-1.15(d, 4.0Hz, 6H), 0.93-0.91(m, 1H), 0.51-0.49(d, 8.0Hz, 2H), 0.13-0.11 (d, 8.0Hz, 2H).
Examples 150 and 151 Preparation of (R)-3-(6-chloro-5-(2-isopropoxypheny1)-1H-benzo [di imidazol-2-y1)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propan-l-ol and (S)-3-(6-chloro-5-(2-isopropoxypheny1)-1H-benzo [di imidazol-2-y1)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propan-l-ol <Leo N
H CI CI
HO HO

HO A.,.......Br l\--..---C) CH2Cl2 a K2CO3/DMF 0 0 0 sv -1-MCPBA 0 9 SH r.7 HO
1. KOH/Me0H LiHMDS/THF
i. 0 SO
2. ______ HCI r'V' 0 Et0...L.,Br Et0 0 0 IW Me0H/H20 Fe, NH4CI
Br NH2 . CI io Br NH2 NH2 Pd2(dba)3, t-Bu3P-BF4 Na2003, dioxane/H20 NH2 0 Et0 0 SO2Et Y

Et0 A.,.......,g,0 H
N HOAc EDCl/HOBt/ DMF N 2N CI CI reflux H
V.0 q Et0 S=0 S=0 N L1AIH4 N Chiral seperation THF
N CI N CI
H
OH
Et0 HO
<c_40 Y <c_go Y

N
li 0 N
/
N CI N CI
H H
HO HO
Step 1: Preparation of cyclopropylmethyl 2-(4-(cyclopropylmethylthio) phenyl)acetate HO .ABr .A\(:) _____________________________________ I

Sv, To a solution of 2-(4-mercaptophenyl)acetic acid (10 g, 59.4 mmol) in DMF (100 mL), was added potassium carbonate (25.0 g, 181.2 mmol) and cyclopropylmethyl bromide (20 g, 148.1 mmol). The reaction mixture was stirred at 50 oC overnight. It was distributed between water and ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and purified on a silica gel column, eluting with 25 % ethyl acetate in hexanes, to get cyclopropylmethyl 2-(4-(cyclopropylmethylthio)phenyl)acetate (15.0 g, 91.3 %
yield) as a colorless oil.

Step2: Preparation of cyclopropylmethyl 2-(4-(cyclopropylmethyl)sulfonyl)phenyl) acetate oH2a2 To a solution of cyclopropylmethyl 2-(4-(cyclopropylmethylthio)phenyl)acetate (15.0 g, 54.3 mmol) in dichloromethane (200 mL), was added MCPBA (23.4 g, 135.6 mmol) at 0 oC.
After addition, the reaction mixture was stirred at ambient temperature for 14 hours. It was distributed between dichloromethane and saturated sodium thiosulfate. The organic layer was washed with 2N aqueous sodium hydroxide solution and brine. It was concentrated and purified on a silica gel column, eluting with 60 % ethyl acetate in hexanes, to get cyclopropylmethyl 2-(4-(cyclopropylmethyl)sulfonyl)phenyl)acetate (12 g, 71.6 % yield) as a white solid.
Step3: Preparation of 2-(4-(cyclopentylmethyl sufonyl)phenyl)acetic acid AO 1. KOH/Me0H HO

rV 2. HCI 0 To a 250 mL round bottom flask, were added cyclopropylmethyl 2-(4-(cyclopropylmethyl)sulfonyl)phenyl)acetate (15.0 g, 48.6 mmol) and methanol (100 mL). a solution of sodium hydroxide in water (3.8 g, 95.0 mmol in 100 ml of water) was added. The reaction mixture was heated to reflux for 12 h. The volatiles were evaporated under reduced pressure. The residue was acidified with IN HCI to pH 3.0 and extracted with ethyl acetate (100 m1x3). The organic layer was separated and combined, washed with brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to get the title compound as a white solid (9.0 g, 72.7%), MS (+) ES: 255 (M+H) .
Step 4. Preparation of 2-(4-((cyclopropylmethyl)sulfonyflpheny1)-4-ethoxy-4-oxobutanoic acid HO
LiHMDS/THF

Br Et0 0 0 Et0 To 2-(4-(cyclopentylmethyl)sufonyl)phenyl)acetic acid (1.0g, 3.9mm01) in THF
(30mL) at -78 C was added LiHMDS(1M in THF, 8.4 mL). After 15min, ethyl 2-bromoacetate (1.0 g, 5.9 mmol) was added. The reaction mixture was stirred at -78oC for 1.0h, then 0.1N HC1 solution was added to adjust pH to 3-4. Extracted with Et0Ac three times, dried over Na2SO4, filtered, concentrated. The residue was purified by silica gel column with elution system A to give yellow oil 0.8 g, MS (ESI): 341 (M+H) .
Step 5. Preparation of 4-bromo-5-chlorobenzene-1,2-diamine CI NO
Fe, NH4CI
Me0H/H20 CI NH
Br NH2 Br NH2 To a solution of 5-bromo-4-chloro-2-nitroaniline (9.0 g, 35.8 mmol) in 250 mL
of methanol and 60 mL of water was added Fe powder (6.0 g, 107.4 mmol) and NH4C1 (5.7 g, 106.5 mmol). The reaction mixture was stirred at 80 C overnight. It was filtered. The filtrate was concentrated, and purified on a silica gel column, eluting with ethyl acetate, to get 4-bromo-5-chlorobenzene-1,2-diamine (6.0 g, 75.7 % yield) as a yellow solid.
Step 6. Preparation of 6-chloro-2'-isopropoxy-11,1'-bipheny11-3,4-diamine Cl NH2 Pd2(dba) t-Bu3P-BF11...
Na2CO3, dioxane/H20 Br NH2 A
mixture of 4-bromo-5-chlorobenzene- 1,2-diamine (1.1 g, 5.0 mmol), (2-isopropoxyphenyl)boronic acid (1.1 g, 6.1 mmol), tris-(dibenzylideneacetone) dipalladium(0) (454 mg), tri(tert-butyl)phosphonium tetrafluoroboronate (288 mg) and sodium carbonate (1.8 g, 14.5 mmol) in 1,4-dioxane (100 ml) and water (10 mL) was degassed, heated to 90 C under for 3h. The volatile solvents were removed under reduced pressure. The residue was directly loaded onto a ISCO solid cartridge and flashed with hexane/ethyl acetate to afford a white solid product 1.1 g (80% yield), MS (+) ES: 277 (M+H) .
Step 7. Preparation of ethyl 4-((4-amino-6-chloro-2'-isopropoxy-11,1'-bipheny11-3-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyl)pheny1)-4-oxobutanoate and ethyl 4-((5-amino-2-chloro-2'-isopropoxy-11,1'-bipheny11-4-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyl)pheny1)-4-oxobutanoate Et0 I2N
EDCl/HOBt/ DMF Et0 CI

0 (:2N CI Et0 To a solution of 6-chloro-2'-isopropoxy41,1'-biphenyll-3,4-diamine (600 mg, 1.76 mmol) and 2-(4-((cyclopropylmethyl)sulfonyl)pheny1)-4-ethoxy-4-oxobutanoic acid (585 mg, 2.11 mmol) in DMF (5 mL) was added EDCI (674 mg, 3.53 mmol), HOBT (537 mg, 3.53 mmol) and DIPEA(455 mg, 3.53 mmol). The reaction solution was stirred at room temperature for .. 2 hours. It was absorbed onto 5 g of silica gel, and loaded onto a silica gel column. The column was eluted with 45 % of ethyl acetate in hexanes to get a mixture of ethyl 4-((4-amino-6-chloro-2'-isopropoxy-111,1'-bipheny11-3-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyl)pheny1)-4-oxobutanoate and ethyl 4-((5-amino-2-chloro-2'-isopropoxy- 111,1'-bipheny11-4-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyl)pheny1)-4-oxobutanoate (750 mg, 71 % yield) as a white solid. MS (ESI): 599 (M+H) .
Step 8. Preparation of ethyl 3-(6-chloro-5-(2-isopropoxypheny1)-1H-benzo [di imidazol-2-34)-3 -(4-((c yc loprop ylmethyl)su lfonyl)phenyl)prop ano ate 0 0 <C_g0 Et0 HOAc N CI reflux (PI Et0 N CI

0 Et0 The mixture of ethyl 4-((4-amino-6-chloro-2'-isopropoxy-111,1'-bipheny11-3-y1) amino)-3-(4-((cyclopropylmethyl)sulfonyl)pheny1)-4-oxobutanoate and ethyl 4-((5-amino-2-chloro-2'-isopropoxy- 111,1 '-b ipheny11-4- yl) amino)-3 -(4-((cycloprop ylmethyl) sulfo nyl)pheny1)-4-oxobutanoate (800 mg) was treated with 15 mL of glacial acetic acid at 80 oC
for 2 hours. It was concentrated, and purified on a silica gel column, eluting with 60 % ethyl acetate in hexanes, to get ethyl 3 -(6-chloro-5 -(2-isopropoxypheny1)- 1H-b enzo [di imidazol-2- y1)-3 -(4-((cyclopropylmethyl)sulfonyl)phenyl)propanoate (700 mg, 90 % yield) as a pale solid. MS
(ESI): 581(M+H) .
Step 9. Preparation of (R)-3-(6-chloro-5-(2-isopropoxypheny1)-1H-benzo [di imidazol-2-y1)-3-(4-((c yclopropylmethyl)sulfo nyl)phenyl)prop an- 1-ol and (S)-3 -(6-chloro-5 -(2-isopropoxypheny1)- 1H-benzo [di imid azol-2- y1)-3 -(4 -((c yc loprop ylmethyl)su lfonyl)phenyl)prop an-1 -ol s=o LiAIH4 Chiral seperation THF
CI CI
OH
Et0 HO

s=o s=o N
) H CI
CI
HO HO
To a solution of ethyl 3-(6-chloro-5-(2-isopropoxypheny1)-1H-benzo [di imidazol-2-y1)-3-(4-((cycloprop ylmethyl)sulfonyl)phenyl)propanoate(440 mg, 0.76 mmol) in THF(20 ml) was added LiA1H4 (29 mg, 0.76 mmol) at 0 C. The reaction mixture was stirred at room temperature for 1 h. 5.0 mL water was added, the mixture was filtered. The filtrate was concentrated, the crude product was purified by flash column chromatography with hexane/ethyl acetate to get the 3-(6-chloro-5-(2-isopropoxyphenye- 1H-benzo ldlimidazol-2-y1)-3 -(4 - ((cyc loprop ylmethyl) sulfonyflphenyl)prop an- I -ol (400 mg).
It was separated chirally (separation conditions: CHIRALCEL OZ-H(OZHOOCD-VC005), 0.46 cm I.D. x 15 cm L; mobile phase: ethanol/hexane=6:4 (v/v); flow rate: 1.0 mL/min), The corresponding fractions were collected and concentrated under reduced pressure to obtain the title compounds (183 mg, 165mg).
Single configuration compound (the shorter retention time) MS (+) ES: 539 (M+H)+;
Chiral HPLC analysis: retention time 6.938 minutes, chiral purity: 100%
(chromatographic column: OD Phenomenex Lux Cellulose-I 150*4.6mm,5um; mobile phase:
ethanol/hexane=40:60 (v/v);
1H NMR (400 mHz, CD30D): 7.90 (d, 8.0Hz, 2 H), 7.67 (d, 8.0 Hz, 2 H), 7.62 (s, 0.5 H), 7.49 (s, 0.5 H), 4.59 (t, 8.0Hz, 1 H), 4.38 (dd, 8.0, 11.0 Hz, 1 H), 4.27-4.11 (m, 1 H), 3.44-3.28 (m, 4 H), 3.20 (q, 8.0Hz, 2 H), 2.24-2.01 (m, 4H), 1.21 (t, 8.0Hz, 3 H).
Single configuration compound (the longer retention time) MS (+) ES: 539 (M+H)+;
Chiral HPLC analysis: retention time 11.098 minutes, chiral purity: 100%
(chromatographic column: OD Phenomenex Lux Cellulose-I 150*4.6mm,5um; mobile phase:
ethanol/hexane=40:60 (v/v);

1H NMR (400 mHz, CD30D): 7.90 (d, 8.0Hz, 2 H), 7.67 (d, 8.0 Hz, 2 H), 7.62 (s, 0.5 H), 7.49 (s, 0.5 H), 4.59 (t, 8.0Hz, 1 H), 4.38 (dd, 8.0, 11.0 Hz, 1 H), 4.27-4.11 (m, 1 H), 3.44-3.28 (m, 4 H), 3.20 (q, 8.0Hz, 2 H), 2.24-2.01 (m, 4H), 1.21 (t, 8.0Hz, 3 H).
Examples 152 and 153 Preparation of (S)-3-(6-chloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo [di imidazol-2-y1)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanamide and (R)-3-(6-chloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo [di imidazol-2-y1)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanamide <L F,F
T
0osi a T

N N
/
N CI i µ N CI

OH

CI i& NH2 Pd2(clba)3, t-Bu3P-BF4 +
Br WI NH2 Na2003, dioxane/H20 NH2 Et0 0 EDCl/HOBt/ DM F
1,,,.../A

F)F 0' F F,F
0 T 0 s T
0 0 Et0 Ag*0 + 0 H 82N HOAc e N
reflux N
VO (PI2N CI Et0 H N CI

0 Et0 .<_ P F,F <C_ FF ):;-) F,F

0 .
NH3 N Chiral seperation W N /1\I
/ = / +
Me0H

Step 1. Preparation of 6-chloro-2'-(difluoromethoxy)-11,1'-bipheny11-3,4-diamine CI 0 NH2 Pd2(dba)3, t-Bu3P-BF4,..

Br NH Na2CO3' dioxane/H20 F)F
A mixture of 4-bromo-5-chlorobenzene-1,2-diamine (1.5 g, 6.78 mmol), 2-(2-(difluoromethoxy)pheny1)-4,4,5,5-tetramethy1-1,3,2-dioxaborolane (2.2 g, 8.15 mmol), tris-(dibenzylideneacetone)dipalladium(0) (620 mg), tri(tert-butyl) phosphonium tetrafluoroboronate (393 mg) and sodium carbonate (1.7 g, 13.7 mmol) in 1,4-dioxane (50 ml) and water (10 mL) was degassed, heated to 90 C under for 3h. The volatile solvents were removed under reduced pressure. The residue was directly loaded onto a ISCO solid cartridge and flashed with hexane/ethyl acetate to afford a white solid product 1.0 g (51.9%
yield), MS (+) ES: 285 (M+H) .
Step 2. Preparation of ethyl 4-((4-amino-6-chloro-2'-(difluoromethoxy)-11,1'-bipheny11-3-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyl)pheny1)-4-oxobutanoate and ethyl 4-((5-amino-2-chloro -2' -(difluorometho xy)-11,1 '-b ipheny11-4- yl) amino)-3 -(4 -((cyclopropylmethyl)sulfonyl)pheny1)-4-oxobutanoate Et0 A,Ch),0 EDCl/HOBt/ Et0 DMF 82N

N CI

0 q2N a Et0 To a solution of 6-chloro-2'-(difluoromethoxy)41,1'-bipheny11-3,4-diamine (543 mg, 1.9 mmol) and 2-(4-((cyclopropylmethyl)sulfonyl)pheny1)-4-ethoxy-4-oxobutanoic acid (500 mg, 1.47 mmol) in DMF (5 mL) was added EDCI (560 mg, 2.93 mmol), HOBT (447 mg, 2.93 mmol) and DIPEA(380 mg, 2.94 mmol). The reaction solution was stirred at room temperature for 2 hours. It was absorbed onto 5 g of silica gel, and loaded onto a silica gel column. The column was eluted with 45 % of ethyl acetate in hexanes to get a mixture of ethyl 4 -((4- amino -6-chloro-2'- (diflu oromethoxy)-11,1' -bipheny11-3 - yl) amino)-3 -(4-((cyclopropylmethyl)sulfonyl)pheny1)-4-oxobutanoate and ethyl 4-((5-amino-2-chloro-2'-(difluoromethoxy)-11,1'-bipheny11-4- yl) amino)-3 - (4 -((cyc loprop ylmethyl) sulfonyl)pheny1)-4-oxobutano ate (600 mg, 62.3 % yield) as a white solid. MS (ESI): 607 (M+H) +.
Step 3. Preparation of ethyl 3-(6-chloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo [di imid azol-2- y1)-3 - (4- ((c yc loprop ylmethyl) su lfonyl)phenyl)prop ano ate F,F
F,F
F,F 0 0 0 s =0 Ag,o Et0 0 82N
HOAc CI reflux (2N a Et0 CI

Et0 The mixture of ethyl 4-((4-amino-6-chloro-2'-(difluoromethoxy)-11,1'-bipheny11-yl)amino)-3-(4-((cyclopropylmethyl)sulfonyl)pheny1)-4-oxobutanoate and ethyl 4-((5-amino-2-chloro -2' -(difluorometho xy)- 111,1 '-b ipheny11-4- yl) amino)-3 -(4 -((cyclopropylmethyl)sulfonyl)pheny1)-4-oxobutanoate (800 mg) was treated with 15 mL of glacial acetic acid at 80 oC for 2 hours. It was concentrated, and purified on a silica gel column, eluting with 60% ethyl acetate in hexanes, to get ethyl 3-(6-chloro-5-(2-isopropoxypheny1)-1H-benzo [di imid azol-2- y1)-3 -(4 -((cyc loprop ylmethyl) sulfonyl) phenyl)propanoate (600 mg, 77.3 % yield) as a pale solid. MS (ESI): 589(M+H) .
Step 4. Preparation of ethyl (S)-3-(6-chloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo [di imid azol-2- y1)-3 - (4- ((c yc loprop ylmethyl) su lfonyl)phenyl)prop anamide and (R)-3 -(6-chloro -5- (2 -(difluorometho xy)pheny1)- 1H-benzo [di imid azol-2- y1)-3 -(4 -((cyclopropylmethyl)sulfonyl)phenyl)propanamide <¨g0 FõF
FõF

* N 0 NH3 Me0H Chiral seperation.-CI
CI

Et0 H2N
AO FõF FõF
* N 0 * N 0 '$ CI N CI

To a solution of ethyl 3 -(6 -chloro-5 -(2- (diflu oromethoxy)pheny1)- 1H-benzo [di imid azol-2- y1)-3 - (4- ((c yc loprop ylmethyl) su lfonyl)phenyl)prop ano ate (400 mg, 0.68 mmol) in methanol(5 ml) was added NH3 (4.8 mL, 7N in methanol, 33.9 mmol). The reaction mixture was stirred at 60 C for 12 h. the mixture was concentrated, the crude product was purified by flash column chromatography with hexane/ethyl acetate to get 3-(6-chloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo [di imid azol-2- y1)-3 - (4-((c yc loprop ylmethyl) su lfonyl)phenyl)prop anamide (177 mg).
It was separated chirally (separation conditions: CHIRALCEL OZ-H(OZHOOCD-VC005), 0.46 cm I.D. x 15 cm L; mobile phase : 100% methanol; flow rate: 1.0 mL/min), The corresponding fractions were collected and concentrated under reduced pressure to obtain the title compounds (67 mg, 60mg).
Single configuration compound (the shorter retention time) MS (+) ES: 560 (M+H) .

Chiral HPLC analysis: retention time 3.919 minutes, chiral purity: 100%
(chromatographic column: OD Phenomenex Lux Cellulose-1 150*4.6mm,5um; mobile phase:
ethanol/hexane=80:20 (v/v);
1H NMR (400 mHz, CD30D): 7.92 (d, 8.0Hz, 2 H), 7.51-7.49 (s, 1H), 7.65 (d, 8.0 Hz, 2 H), 7.56-7.54 (m, 1H), 7.48-7.44 (m, 1H), 7.33-7.32 (m, 2H), 7.28-7.26 (d, 8.0Hz, 1H), 6.86 (d, 8.0Hz, 1H), 4.96-4.92 (t, 8.0Hz, 1H), 3.41-3.35 (dd, 8.0Hz, 1H), 3.13-3.11 (d, 8.0Hz, 2H), 3.12-3.06 (dd, 8.0Hz, 1H), 0.93-0.91 (m, 1H), 0.52-0.50 (d, 8.0Hz, 2H), 0.13-0.11 (d, 8.0Hz, 2H).
Single configuration compound (the longer retention time) MS (+) ES: 560 (M+H)+;
Chiral HPLC analysis: retention time 8.942 minutes, chiral purity: 100%
(chromatographic column: OD Phenomenex Lux Cellulose-1 150*4.6mm, Sum; mobile phase:
ethanol/hexane=80:20 (v/v);
1H NMR (400 mHz, CD30D): 7.92 (d, 8.0Hz, 2 H), 7.51-7.49 (s, 1H), 7.65 (d, 8.0 Hz, 2 H), .. 7.56-7.54 (m, 1H), 7.48-7.44 (m, 1H), 7.33-7.32 (m, 2H), 7.28-7.26 (d, 8.0Hz, 1H), 6.86 (d, 8.0Hz, 1H), 4.96-4.92 (t, 8.0Hz, 1H), 3.41-3.35 (dd, 8.0Hz, 1H), 3.13-3.11 (d, 8.0Hz, 2H), 3.12-3.06 (dd, 8.0Hz, 1H), 0.93-0.91 (m, 1H), 0.52-0.50 (d, 8.0Hz, 2H), 0.13-0.11 (d, 8.0Hz, 2H).
Example 154 Preparation of 3 -(4-((c yc loprop ylmethyl)su lfonyl)pheny1)-3 -(5 ,7-dichloro-6-(4,4 -difluorop iperidin- 1 - y1)-1H-benzo [di imidazol-2-yl)propanamide CI
FFK
CI N

CI CI
0õ0 FN =

N FF.CN=

N,Boc CI N Cl CI CI
FN

= N,Boc s FN

W N

CI N CI N

Step 1. Preparation of tert-butyl 4,6-dichloro-2-(4-((cyclopropylmethyl)sulfonyflbenzy0-5-(4,4-difluoropiperidin- 1 - y1)- 1H-b enzo [di imidazo le- 1-c arbo xylate CI CI
Boc C
0 ,0 FF-CN N .1 -p..
F N= NS \__4 N ci N
To a solution of 2-(4- (cycloprop ylmethylsulfonyflb enzy1)-5 ,7-dichloro-6- (4,4-.. difluoropiperidin-1-y0-1H-benzo [d] imidazole (3.35 g, 6.51 mmol) in DCM
(25 mL) was added Boc anhydride (1.25 g, 9.77 mmol), DIEA (1.7 mL, 9.77mm01), and catalytic amount of DMAP, at ambient temperature. After addition, the reaction solution was stirred at ambient temperature over night. It was concentrated. The residue was purified on a silica gel column, eluting with 25 % Et0Ac in DCM, to get a mixture of two isomers of the product as a pale solid (10.7 g, 90 % yield).
MS (+) ES: 614 (M+H) .
Step 2. Preparation of tert-butyl 4,6-dichloro-2-(1-(4-((cyclopropylmethyl) sulfonyflpheny1)-3 -methoxy-3 -oxoprop y1)-5 - (4,4 -difluorop iperidin-1 - y1)- 1H-benzo [di imid azo le- 1 -c arboxyl ate CI
CI 0 ,0 0 V--\N N,Boc op F\rTh. /\ =N F--"\_11 'Bc)c µ0:.--4 CI N CI N

To a solution of tert-butyl 2-(4-(cyclopropylmethylsulfonyflbenzy0-4,6-dichloro-5-(4,4-difluoropiperidin-1-y0-1H-benzo [di imidazole-l-carboxylate (465 mg, 0.76 mmol) in dry THF (10 mL) was added lithium hexamethyldisilyl amide solution (1M, 1 mL, 1 mmol), at -78 C. After it was stirred at -78 C for 30 minutes, methyl bromoethylacetate (233 mg, 1.52 mmol) was added, and the reaction solution was slowly warmed to ambient temperature, and stirred over night. It was worked up with Et0Ac and water. The organic layer was concentrated and purified on a silica gel column, eluting with 25 % of Et0Ac in DCM to get the desired product as a white solid (511 mg, 98 % yield). MS (+) ES: 686 (M+H) .
Step 3. Preparation of 3 -(4- ((c ycloprop ylmethyl) sulfo nyflpheny1)-3 -(5 ,7 -dichloro-6 -(4,4-difluorop iperidin- 1 - y1)- 1H-benzo [di imid azol-2- yl)prop anamide C
Cl I
0õ0 0õ0 FN

=

N,Boc ksc_4 FF. N =
N N S
CI N CI

A solution of tert-butyl 4 ,6 -dichloro -2-(1 -(4- (c ycloprop ylmethyl) sulfo nyl)pheny1)-3 -metho xy-3 -oxoprop y1)-5 -(4 ,4-diflu oropip eridin- 1 -y1)- 1H-b enzo [di imidazole- 1 -c arbo xylate (1 g, 1.45 mmol) in 20 mL of methanol (containing about 7 N ammonia) in a sealed reaction flask was stirred at 80 C for 10 hours. It was concentrated and purified on a silica gel column, eluting with Et0Ac to get the desired product as a white solid (0.65 g, 78 %
yield). MS (+) ES: 571 (M+H) .
Examples 155 and 156 Preparation of (S)-3-(6-chloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo ldlimidazol-2- y1)-3 -(4-((c yc loprop ylmethyl) su lfonyl)phenyl)prop an-1 -ol and (R)-3 - (6-chloro-5- (2- (diflu oro methoxy)pheny1)- 1H-benzo [di imidazol-2 -y1)-3 -(4 -((c yc loprop ylmethyl) su lfonyl)phenyl)prop an-1 -ol FF <c_ p FF
O 0 e /1\I
N CI N CI
H

F,F <c_ F,F <c_ F,F
0 0 (? 0 OP 0 LiAlH4 /1\I Chiral seperation THF
CI CI CI

Et0 HO HO
F,F

CI
) H
HO
To a solution of ethyl 3-(6-chloro-5-(2-isopropoxypheny1)-1H-benzo [di imidazol-2-y1)-3-(4-((cycloprop ylmethyl)sulfonyl)phenyl)propanoate(550 mg, 0.93 mmol) in THF (15 ml) was added LiA1H4 (35 mg, 0.93 mmol)at 0 C. The reaction mixture was stirred at room temperature for 1 h. 5.0 mL water was added, the mixture was filtered. The filtrate was concentrated, the crude product was purified by flash column chromatography with hexane/ethyl acetate to get 3-(6-chloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo lidlimidazol-2-yl)-3 - (4-((c yc loprop ylmethyl) su lfo nyl)phenyl)prop an- 1 -ol (250 mg).

It was separated chirally (separation conditions: CHIRALCEL OZ-H(OZHOOCD-VC005), 0.46 cm I.D. x 15 cm L; mobile phase : 100% Hexane/Ethano1=80/20(V/V);
flow rate: 1.0 mL/min), The corresponding fractions were collected and concentrated under reduced pressure to obtain the title compounds (110 mg, 100 mg).
Single configuration compound (the shorter retention time) MS (+) ES: 547 (M+H)+;
Chiral HPLC analysis: retention time 6.374 minutes, chiral purity: 100%
(chromatographic column: CHIRALPAK IG 150*4.6mm, Sum; mobile phase: ethanol/hexane=20:80 (v/v);
1H NMR (400 mHz, CD30D): 7.94-7.92 (d, 8.0Hz, 2 H), 7.67-7.65 (d, 8.0 Hz, 2 H), 7.48-7.44 (m, 2H), 7.32-7.31 (m, 2H), 7.27-7.25 (m, 2H), 6.84-6.47 (t, 1H), 4.71-4.67 (t, 8.0Hz, 1H), 3.64-3.53 (m, 1H), 3.13-3.12 (d, 4.0Hz, 2H), 2.68-2.57 (m, 1H), 2.40-2.31 (m, 1H), 1.32-1.30 (m, 2H), 0.99-0.89 (m, 1H), 0.53-0.48 (q, 2H), 0.14-0.10 (q, 2H).
Single configuration compound (the longer retention time) MS (+) ES: 547 (M+H)+;
Chiral HPLC analysis: retention time 7.719 minutes, chiral purity: 100%
(chromatographic column: CHIRALPAK IG 150*4.6 mm, 5 um; mobile phase: ethanol/hexane=20:80 (v/v);
1H NMR (400 mHz, CD30D): 7.94-7.92 (d, 8.0Hz, 2 H), 7.67-7.65 (d, 8.0 Hz, 2 H), 7.48-7.44 (m, 1H), 7.32-7.31 (m, 2H), 7.27-7.25 (m, 2H), 6.84-6.47 (t, 1H), 4.71-4.67 (t, 8.0Hz, 1H), 3.64-3.53 (m, 1H), 3.13-3.12 (d, 4.0Hz, 2H), 2.68-2.57 (m, 1H), 2.40-2.31 (m, 1H), 1.32-1.30 (m, 2H), 0.99-0.89 (m, 1H), 0.53-0.48 (q, 2H), 0.14-0.10 (q, 2H).
Example 157 Preparation of 3 -(4-((c yc loprop ylmethyl)sulfonyl)pheny1)-3 -(5 ,7-dichloro-6-(4,4 -difluorop iperidin- 1 - y1)-1H-b enzo [di imidazol-2 - yl)prop an- 1 -ol CI
/-\NI /m\
W S
CI N
OH

This compound was prepared by the similar method as of example 139,140 (racemic mixture) to produce the title compound as a white solid. MS (+) ES: 558 (M+H) .
Example 158 Preparation of 3-(4-((cyclopropylmethyl)sulfonyl)pheny1)-3-(5,7-dichloro-6-(2-(difluoromethoxy)pheny0-1H-benzo [di imidazol-2-yl)propanamide oõo \s'¨\

This compound was prepared by the similar method as of Examples 148, 149 (racemic mixture) to produce the title compound as a white solid. MS (+) ES: 594 (M+H) .
Example 159 Preparation of 3-(4-((cyclopropylmethyl)sulfonyl)pheny1)-3-(5,7-dichloro-6-(2-(difluoromethoxy)pheny0-1H-benzo [di imidazol-2-yl)propan-l-ol CI
OH

This compound was prepared by the similar method as of example 150,151 (racemic mixture) to produce the title compound as a white solid. MS (+) ES: 581 (M+H) .

Examples 160 and 161 Preparation of (S)-3 -(4-((c ycloprop ylmethyl) sulfo nyl)pheny1)-3 -(5,7 -dichloro-6-(4,4-diflu oropip eridin- 1 -y1)- 1H-benzo [di imid azol-2- yl)prop an- 1 -ol (R)-3 -(4-((c ycloprop ylmethyl) sulfo nyl)pheny1)-3 -(5 ,7-dichloro-6-(4,4-difluorop ip eridin-1 - y1)-1H-b enzo [di imid azol-2-yl)prop an-l-ol ci c F
CI N ci N
H
( OH OH

F CI F CI F CI
0 0 Oss,/0 Oss,/0 FN N F-CN = y 40 S\.---4 FN
ssS-4 I VI
CI N ChraI seperaton CI N CI
.1111P
OH OH OH

These two compounds were prepared from example 157 by chirally separation.
(separation conditions: CHIRALCEL OZ-H(OZHOOCD-VC005), 0.46 cm I.D. x 15 cm L;
mobile phase : 100% Hexane/Ethano1=70/30(V/V); flow rate: 1.0 mL/min), The corresponding fractions were collected and concentrated under reduced pressure to obtain the title compounds (350 mg, 350 mg).
Single configuration compound (the shorter retention time) MS m/z (ESI): 557.9 1M+11;
Chiral HPLC analysis: retention time 7.378 minutes, chiral purity: 100%
(chromatographic column: OD Phenomenex Lux Cellulose-1 150*4.6mm, Sum; mobile phase:
ethanol/hexane=15:85 (v/v);
1H NMR (400 mHz, CD30D): 7.91 (d, 2H), 7.66 (d, 2H), 7.44-7.40 (m, 1H), 4.68-4.66 (m, 1H), 3.55-3.53 (m, 2H), 3.13-3.11 (m, 2H), 2.68-2.57 (m, 2H), 2.40-2.31 (m, 2H), 2.11-2.14 (m, 4H), 1.32-1.30 (m, 1H), 0.91-0.89 (m, 2H), 0.50 (q, 2H), 0.12 (q, 2H).
Single configuration compound (the longer retention time) MS m/z (ESI): 557.9 1M+11;
Chiral HPLC analysis: retention time 8.738 minutes, chiral purity: 100%
(chromatographic column: OD Phenomenex Lux Cellulose-1 150*4.6mm, Sum; mobile phase:
ethanol/hexane=15:85 (v/v);
1H NMR (400 mHz, CD30D): 7.91 (d, 2H), 7.66 (d, 2H), 7.44-7.40 (m, 1H), 4.68-4.66 (m, 1H), 3.55-3.53 (m, 2H), 3.13-3.11 (m, 2H), 2.68-2.57 (m, 2H), 2.40-2.31 (m, 2H), 2.11-2.14 (m, 4H), 1.32-1.30 (m, 1H), 0.91-0.89 (m, 2H), 0.50 (q, 2H), 0.12 (q, 2H).

Examples 162 and 163 Preparation of (S)-3 -(4- ((c ycloprop ylmethyl) sulfo nyl)pheny1)-3 -(5,7 -dichloro-6- (4,4-diflu oropip eridin- 1 -y1)- 1H-benzo [di imid azol-2- yl)prop anamide (R)-3 - (4- ((c yc loprop ylmethyl)su lfo nyl)pheny1)-3 -(5 ,7-dichloro-6-(4,4-difluorop ip eridin- 1 -y1)- 1H-benzo [di imid azol-2- yl)prop anamide FN

CIN
H

CI CI CI

FN = S FN = FN= S
CIN CI
0 0 ( These two compounds were prepared from example 154 by chirally separation.
(separation conditions: CHIRALCEL OZ-H(OZHOOCD-VC005), 0.46 cm I.D. x 15 cm L;

mobile phase : 100% Hexane/Ethano1=45/55(V/V); flow rate: 1.0 mL/min), The corresponding fractions were collected and concentrated under reduced pressure to obtain the title compounds (250 mg, 250 mg).
Single configuration compound (the shorter retention time) MS m/z (ESI): 571.0 1M+11;
Chiral HPLC analysis: retention time 8.193 minutes, chiral purity: 100%
(chromatographic column: OD Phenomenex Lux Cellulose-1 150*4.6mm, Sum; mobile phase:
ethanol/hexane=15:85 (v/v);
1H NMR (400 mHz, CD30D): 7.90 (d, 2H), 7.65-7.63 (m, 3H), 4.94-4.92 (m, 1H), 3.13-3.03 (m, 3H), 2.68-2.57 (m, 1H), 2.40-2.31 (m, 2H), 2.11-2.14(m, 4H), 1.38-1.30 (m, 1H), 0.94-0.91 (m, 2H), 0.50 (q, 2H), 0.11 (q, 2H).
Single configuration compound (the longer retention time) MS m/z (ESI): 571.0 1M+11;
Chiral HPLC analysis: retention time 10.536 minutes, chiral purity: 100%
(chromatographic column: OD Phenomenex Lux Cellulose-1 150*4.6mm, Sum; mobile phase:
ethanol/hexane=15:85 (v/v);

1H NMR (400 mHz, CD30D): 7.90 (d, 2H), 7.65-7.63 (m, 3H), 4.94-4.92 (m, 1H), 3.13-3.03 (m, 3H), 2.68-2.57 (m, 1H), 2.40-2.31 (m, 2H), 2.11-2.14(m, 4H), 1.38-1.30 (m, 1H), 0.94-0.91 (m, 2H), 0.50 (q, 2H), 0.11 (q, 2H).
Examples 164 and 165 Preparation of (S)-4-(3-(6-chloro-5-(2-(difluoromethoxy)pheny1)-1H-benzoldlimidazol-2-y1)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propyl)morpholine (R)-4-(3-(6-chloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo kllimidazol-2-y1)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propyl)morpholine <c_ FI,F
I,F
,P
F

W W
H c i <c_ s FF <c_ s F,i0õF <c_g FF
O'm, W /1\I eWm. sm. W /1\I
N CI N CI 0H a Et0 Et0 Et0 DIBAL-Hi DIBAL-H i DCM
DCM

C¨,g9 F,i0õ F <c_i FF
0', O'W
N
N
/
N CI 0H a OH
H
H
NaBH(0A1 NaBH(OAc)3 HOAc HOAc DCM
DCM
<L <c_ s F,T).F ,s FF
em, em, W N W /NI
HN a H a cr) 0 Step 1. Preparation of ethyl (R or S)-3-(6-chloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo[d] imidazol-2-y1)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanoate <
c_ s FF <c_ s F <c_ e e F,or, s e w w . w /NI N N
/
OH OH O CIH
Et0 Et0 Et0 These two compounds were prepared by chirally separation. (separation conditions:
CHIRALPAK IB-N(IBN5CD-VD005), 0.46 cm I.D. x 15 cm L; mobile phase : 100%
Hexane/Ethano1=80/20(V/V); flow rate: 1.0 mL/min), The corresponding fractions were collected and concentrated under reduced pressure to obtain the title compounds (690 mg, 490 mg).
Single configuration compound Int-164A (the shorter retention time) MS m/z (ESI): 589.1 [M+11;
Chiral HPLC analysis: retention time 11.508 minutes, chiral purity: 100%
(chromatographic column: CHIRALPAK IG150*4.6mm, Sum; mobile phase: ethanol/hexane=20:80 (v/v);
Single configuration compound Int-164B (the longer retention time) MS m/z (ESI): 589.1 [M+11;
Chiral HPLC analysis: retention time 17.164 minutes, chiral purity: 100%
(chromatographic column: CHIRALPAK IG150*4.6mm, Sum; mobile phase: ethanol/hexane=20:80 (v/v).
Step 2(1). Preparation of (R or S)-3 -(6-chloro-5 -(2 -(difluoro methoxy)pheny1)- 1H-benzo [di imid azol-2- y1)-3 - (4- ((c yc loprop ylmethyl) su lfonyl)phenyl)prop anal o o DIBAL-H
DCM
CI CI
OH OH
Et0 Ethyl (R or S)-3 - (6-chloro -5- (2 -(difluoromethoxy)pheny1)- 1H-benzo [di imid azol-2- y1)-3 -(4-((cyclopropylmethyl)sulfonyl)phenyl)propanoate(the shorter retention time) (step 1) (45 mg, 0.076 mmol) was dissolved in DCM (3.0 mL), diisobutylaluminium hydride (0.16 mL, 0.16 mmol) was added and the mixture was stirred for 30 mm until completion.
The product was purified by flash chromatography with hexane/ethyl acetate to afford a white solid (22 mg, 52%), MS m/z (ESI): 543.0 [M-11.
Step 3(1). Preparation of (R or S)-4-(3 -(6 -chloro-5 -(2- (difluorometho xy)pheny1)- 1H-benzo [di imid azol-2- y1)-3 - (4- ((c yc loprop ylmethyl) su lfonyl)phenyl)prop yl)morpholine FF
F.,TF
NaBW0A03 =
W HOAc DCM
N CI
N CI
OH

(R or S)-3 -(6 -chloro-5 -(2- (difluorometho xy)pheny1)-1H-benzo [di imid azol-2- y1)-3 -(4-((cyclopropylmethyl)sulfonyl)phenyl)propanal(step 2(1)) (22 mg, 0.04 mmol) and Morpholine (17 mg, 0.20 mmol)was dissolved in DCM (5.0 mL), acetic acid (14 mg, 0.24 mmol) was added and the mixture was stirred for 0.5h, NaBH(OAc)3 (25 mg, 0.12 mmol) was added at room temp. The mixture was stirred for 60 mm until the completion (LC-MS
monitor). The mixture was treated with small amount of diluted HC1 and directly purified by flash chromatography with hexane/ethyl acetate to afford a white solid (7.3 mg, 29%), MS m/z (ESI): 616.0 [M+11.
1H NMR (400 mHz, CDC13): 7.99 (d, 2 H), 7.72 (s, 1H), 7.50 (s, 1H), 7.46-7.44 (m, 1H), 7.43 (d, 2H), 7.36-7.33 (m, 2H), 7.31-7.27 (m, 1H), 6.42 (d, 1H), 4.69 (t, 1H), 3.85-3.83 (m, 4H), 3.03-3.01 (m, 2H), 2.60-2.58 (m, 4H), 2.50-2.45(m, 4H), 2.39-2.35 (m, 1H), 1.03-0.98 (m, 1H), 0.60 (d, 2H), 0.19 (d, 2H).
Step 2(2). Preparation of (R or S)-3-(6-chloro-5 -(2- (diflu oro methoxy)pheny1)- 1 H-benzo[d] imid azol-2- y1)-3 - (4- ((c yc loprop ylmethyl) su lfonyl)phenyl)prop anal DIBAL-H
DCM
CI CI
OH OH
Et Ethyl (R or S)-3 -(6 -chloro-5 - (2- (difluorometho xy)pheny1)- 1H-b enzo [di imidazol-2- y1)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanoate (the longer retention time) (example 164, stepl) (100 mg, 0.17 mmol) was dissolved in DCM (10.0 mL), diisobutylaluminium hydride (1.0 mL, 0.1 mmol) was added and the mixture was stirred for 30 mm until completion. The mixture was treated with small amount of diluted HC1 and directly purified by flash chromatography with hexane/ethyl acetate to afford a white solid (50 mg, 54%).
MS m/z (ESI): 543.0 [M-11.
Step 3(2). Preparation of (R or S)-4-(3 -(6 -chloro-5 - (2- (difluorometho xy)pheny1)- 1H-b enzo [di imidazol-2- y1)-3 -(4-((cyclopropylmethyl)sulfonyl)phenyl)prop yl)morpholine F,cr:
F,cr:
NaBH(OAc)3 =
HOAc DCM
N CI
N CI

(R or S)-3-(6-chloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo [di imidazol-2-y1)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanal(step 2(2)) (30 mg, 0.06 mmol) and Morpholine (48 mg, 0.55 mmol) was dissolved in DCM (10.0 mL), acetic acid (33 mg, 0.55 mmol) was added and the mixture was stirred for 0.5h, NaBH(OAc)3 (70 mg, 0.33 mmol) was added at room temp. The mixture was stirred for 60 min until the completion (LC-MS
monitor). The mixture was treated with small amount of diluted HC1 and directly purified by flash chromatography with hexane/ethyl acetate to afford a white solid (13.7 mg, 40%), MS m/z (ESI): 616.0 [M+1].
1H NMR (400 mHz, CDC13): 7.89 (d, 2H), 7.72 (s, 1H), 7.50 (s, 1H), 7.46-7.44 (m, 1H), 7.43 (d, 2 H), 7.36-7.33 (m, 2H), 7.31-7.27 (m, 1H), 6.42 (d, 1H), 4.69 (t, 1H), 3.85-3.83 (m, 4H), 3.03-3.01 (m, 2H), 2.60-2.58 (m, 4H), 2.50-2.45 (m, 4H), 2.39-2.35 (m, 1H), 1.03-0.98 (m, 1H), 0.60 (d, 2H), 0.19 (d, 2H).
Example 166, 167 Preparation of (S)-N-(3-(6-chloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo [di imidazol-2-y1)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propyl)acetamide (R)-N-(3-(6-chloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo [di imidazol-2-y1)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propyl)acetamide F.T,F .<_ F.....iõF
,P ,P
N
N
i .F
N ci Fri CI
H
HoNl_ HoNl_ .(L
s F,10,F <Li NH3 & FF <c_ O'P F,s, F
0' V
NaBH4 CH3COCI *
W HOAc N Et3N N
/1\1 Me0H / DCM /
N CI N CI
N CI H H
H

H
(i¨

<L
s O F F F
,10,F
NH3 & T <Li ' F,T,, F

W
0' NaBH4 W CH3COCI * HOAc N Et3N N
N CI hl CI hl CI

H
(i-

172 Step 1(1) Preparation of (R or S)-3 -(6-chloro-5 - (2-(diflu oro methoxy)pheny1)- 1H-benzokllimid azol-2- y1)-3 - (4- ((c yc loprop ylmethyl) su lfonyl)phenyl)prop an- 1 - amine FF

,s 0 0 NaBH4 HOAc Me0H iN
CI
CI
OH

(R or S)-3 -(6-chloro-5 -(2- (difluorometho xy)pheny1)-1H-benzo azol-2- y1)-3 -(4-((cyclopropylmethyl)sulfonyl)phenyl)propanal(example164,165, step 2(1)) (45 mg, 0.08 mmol) was dissolved in Me0H (3.0 mL), acetic acid (50 mg, 0.83 mmol) and 7N
NH3 in Me0H(1.2 mL, 8.4 mmol)were added and the mixture was stirred for 0.5h, NaBH4 (31 mg, 0.84 mmol) was added at room temp. The mixture was stirred for 60 min until the completion (LC-MS monitor). The mixture was treated with small amount of diluted HC1 and directly purified by flash chromatography with hexane/ethyl acetate to afford a white solid (45 mg, 99%), MS m/z (ESI): 546.1 [M+11.
Step 2(1). Preparation of (R or S)-N-(3 -(6-chloro-5-(2-(difluoromethoxy)pheny1)-1 H-benzokllimid azol-2- y1)-3 - (4- ((c yc loprop ylmethyl) su lfonyl)phenyl)prop yl) acetamide F,T, F FF
hNI 0 0 0 0 Et3N
/1\I
DCM
N CI N CI
HN HN
(R or S)-3 -(6-chloro-5 - (2- (difluorometho xy)pheny1)- 1H-b enzo y1)-3 -(4-((cyclopropylmethyl)sulfonyl)phenyl)propan-1 -amine(45 mg, 0.083 mmol) was dissolved in DCM (2.0 mL), acetyl chloride (8.0 mg, 0.1 mmol) was added followed by the addition of Et3N(9.0 mg, 0.1 mmol)and the mixture was stirred for 0.5h, The mixture was treated with small amount of diluted HC1 and directly purified by Prep HPLC with elution system C to afford the product as a white solid (10.7mg, 22%), MS m/z (ESI):587.9 [M+11.
1H NMR (400 mHz, CD30D): 7.93 (d, 2H), 7.74-7.72 (m, 1H), 7.67-7.65 (m, 2H), 7.57-7.53 (m, 1H), 7.48-7.44 (m, 1H), 7.32(d, 2H), 7.28-7.26 (m, 1H), 6.66 (d, 1H), 4.61 (s, 1H), 4.51-

173 4.47 (m, 1H), 3.25-3.33 (m, 2H), 3.13 (d, 2H), 2.67-2.58 (m, 2H), 2.41-2.31 (m, 2H), 0.97-0.91 (m, 1H), 0.50 (q, 2H), 0.11 (q, 2H).
Step 1(2). Preparation of (R or S)-3-(6-chloro-5 -(2- (diflu oro methoxy)pheny1)- 1 H-benzo[d] imid azol-2- y1)-3 - (4- ((c yc loprop ylmethyl) su lfonyl)phenyl)prop an- 1 - amine FF
FF

0 0 NaBH4 HOAc Me0H
N CI
N CI

(R or S)-3 -(6-chloro-5 - (2- (difluorometho xy)pheny1)- 1H-benzo [di imid azol-2- y1)-3 -(4 -((cyclopropylmethyl)sulfonyl)phenyl)propanal(example164,165, step 2(2)) (50 mg, 0.09 mmol) was dissolved in Me0H (5.0 mL), acetic acid (55 mg, 0.92 mmol) and 7N
NH3 in Me0H(1.3 mL, 9.2 mmol) were added and the mixture was stirred for 0.5h, NaBH4 (21 mg, 0.55 mmol) was added at room temp. The mixture was stirred for 60 mm until the completion (LC-MS monitor). The mixture was treated with small amount of diluted HC1 and directly purified by flash chromatography with hexane/ethyl acetate to afford a white solid (45 mg, 90%), MS m/z (ESI): 546.1 1M+11.
Step 2(2). Preparation of (R or S)-N-(3-(6-chloro-5-(2-(difluoromethoxy)pheny1)-1H-benzo[d]imidazol-2- y1)-3 - (4- ((c yc loprop ylmethyl) su lfonyl)phenyl)prop yl)acetamide F,T., F
F,T., F

Et3N
DCM
N C N CI

(R or S)-3 -(6 -chloro-5 - (2- (difluorometho xy)pheny1)- 1H-b enzo [di imidazol-2-y1)-3 -(4-((cyclopropylmethyl)sulfonyl)phenyl)propan-1 -amine(40 mg, 0.073 mmol) was dissolved in DCM (5.0 mL), acetyl chloride (7.0 mg, 0.09 mmol) was added followed by the addition of Et3N(15 mg, 0.15 mmol) and the mixture was stirred for 0.5h, The mixture was treated with small amount of diluted HC1 and directly purified by Prep HPLC with elution system C to afford the product as a white solid (20mg, 46%) MS m/z (ESI):587.9 1M+11.

174 1H NMR (400 mHz, CD30D): 7.93(d, 2H), 7.74-7.72 (m, 1H), 7.67-7.65 (m, 2H), 7.57-7.53 (m, 1H), 7.48-7.44 (m, 1H), 7.31 (d, 2H), 7.28-7.26 (m, 1H), 6.66 (d, 1H), 4.61 (s, 1H), 4.51-4.47 (m, 1H), 3.25-3.33 (m, 2H), 3.13 (d, 2H), 2.67-2.58 (m, 2H), 2.41-2.31 (m, 2H), 0.97-0.91 (m, 1H), 0.50 (q, 2H), 0.11 (q, 2H).
Example 168 Preparation of N-(3-(5-chloro-6-(2-(difluoromethoxy)pheny1)-1H-benzoldlimid az ol- 2 - yl) -3 -(4-((cyclopropylmethyl)sulfonyl)phenyl)propyl)acetamide ic)P

NH

This compound can be prepared by the similar method as of example 166,167 from corresponding racemic starting material.
Example 169 Preparation of 4-(3-(5-chloro-6-(2-(difluoromethoxy)pheny1)-1H-benzo [di imidazol-2-y1)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propyl)morpholine \e¨\
FloCI
11)) This compound can be prepared by the similar method as of example 164,165 from corresponding racemic starting material.

175 Example 170 Preparation of 4-(3 - (4-((c ycloprop ylmethyl) sulfo nyflpheny1)-3 - (5 ,7 -dichloro-6- (4,4-diflu oropip eridin- 1 - y1)-1H-b enzo [di imidazol-2 - yl)prop yl)morpholine oi o.µk -s \N 4ft N

CI N
Co) Step 1, preparation of cyclopropylmethyl 2-(4-((cyclopropylmethyl)thio)phenyl)acetate HO Br SH 0 sv, To a solution of 2-(4-mercaptophenyl)acetic acid (20 G, 118.9 mmol)in DMF (200 mL) was added (bromomethyl)cyclopropane (40.1G, 297.2 mmol) and cesium carbonate (117 G, 356.7 mmol). After addition, the reaction was stirred at ambient temperature for 14 hours. The reaction mixture was concentrated to remove about half of the solvent. Then, it was worked up with Et0Ac and water. The organic layer was concentrated, and purified on a silica gel column, eluting with 25 % of Et0Ac in hexanes, to get cyclopropylmethyl 2-(4-(cyclopropylmethylthio)phenyl)acetate (26.5 G, 81 % yield) as a colorless oil.
Step 2 preparation of cyclopropylmethyl 2-(4-((cyclopropylmethyl)sulfonyl)phenyl) acetate '6NO

%0 To a solution of cyclopropylmethyl 2-(4-(cyclopropylmethylthio)phenyl)acetate (31 g, 112.3 mmol) in dichloromethane (200 mL) was added meta-chloroperbenzoic acid (58 g, mmol). After addition, the reaction was stirred at ambient temperature for 10 hours. It was distributed between DCM (1L) and aqueous saturated Na2S203 (1 L). The organic layer was washed with 2N sodium hydroxide (200 mL) and brine. It was concentrated, and purified on a silica gel column, eluting with 60 % of Et0Ac in hexanes, to get cyclopropylmethyl 2-(4-(cyclopropylmethylsulfonyl)phenyl)acetate (33.5 G, 96.7 % yield) as a white solid.

176 Step 3 preparation of 2-(4-((cyclopropylmethyl)sulfonyl)phenyl)acetic acid HO

0"0 V
A mixture of cyclopropylmethyl 2-(4-(cyclopropylmethylsulfonyl)phenyl)acetate (32.6 G105.7 mmol) and lithium hydroxide monohydrate (17.8 G, 423 mmol) in 1,4-dioxane (200 mL) and water (60 mL) was stirred at ambient temperature for 10 hours. It was acidified with concentrated hydrochloric acid to pH 5, and extracted with Et0Ac (3 X 300 mL).
The combined organic layers was concentrated to get the desired product, 2-(4-(cyclopropylmethylsulfonyl)phenyl)acetic acid (26.3 G, 98 % yield), as a white solid.
Step 4 preparation of 2,3,4-trichloro-6-nitroaniline =
NCS
C

Cl A suspension of 4,5-dichloro-2-nitrobenzenamine (30 G, 145 mmol), and NCS
(24.2 G, 181.2 mmol) in DMF (250 mL) was heated to 100 oC for 2 hours. It was poured into ice-water. The bright yellow precipitate , 2,3,4-trichloro-6-nitrobenzenamine, was collected by filtration, and high vacuum drying overnight. (34.2 G, 98 % yield).
Step 5 preparation of 2,4-dichloro-3 -(4,4-diflu oropip eridin-1 - y1)-6-nitro aniline NH2 Fr NH CI
CI CI _______________ F
FC

To a solution of (2,3,4-trichloro-6-nitrobenzenamine (5 G, 20.7 mmol) in 30 mL
of DMF, was added 4,4-difluoropiperidine (3.8 G, 31.06 mmol) and DIEA (11.8 mL, 62.1 mmol). The reaction was stirred at 105 C for 2 days. TLC showed mostly product. The majority of the DMF was vacuum removed. Then , it was absorbed onto silica gel, and purified on a silica gel column, eluting with 30% Et0Ac in hexanes, to get the desired product, 2,4-dichloro-3-(4,4-difluoropiperidin-1-y1)-6-nitrobenzenamine, as a brightly yellow solid (4.72 G, 70 %
yield).

177 Step 6 preparation of 3,5 -dichloro -4-(4 ,4-diflu oropip eridin- 1 - yl)b enze ne- 1 ,2-diamine CI CI
FC NO2 Zn / HC1 F)CN
N * NH2 To a suspension of 2,4-dichloro-3-(4,4-difluoropiperidin-1-y1)-6-nitrobenzenamine (3.5 G, 10.8 mmol) in THF (30 mL) was added zinc powder (7 G, 108 mmol) and concentrated HC1 (2 mL). The reaction mixture was stirred at room temperature for 14 hours. It was filtered and the filtrate was concentrated and purified on a silica gel column, eluting with straight Et0Ac, to get 3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)benzene-1,2-diamine as a pale solid (1.83 G, 57 % yield).
Step 7 preparation of N- (2- amino -3 ,5 -dichloro -4-(4 ,4-difluoropiperidin-1 - yl)phe ny1)-2 - (4-((cyclopropylmethyl)sulfonyl)phenyl)acetamide ci ci FcN

0 0 FF)CN

,S(= 0 0"0 0"0 V
To a solution of 2-(4-(cyclopropylmethylsulfonyl)phenyl)acetic acid (1.71 g, 6.71 mmol) in dichloromethane (20 mL) was added EDC (1.61 g, 8.40 mmol), HBTU (3.15 G, 8.40 mmol), followed by 3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)benzene-1,2-diamine (1.65 G, 5.59 mmol). After addition, the reaction solution was stirred at ambient temperature for 2 hours. It was absorbed onto silica gel and eluted with 50 % ethyl acetate in hexanes to get N-(2-amino-3,5 -dichloro-4 - (4,4-difluorop iperidin- 1 - yl)phenyl) -2- (4-(c ycloprop ylmethylsu lfonyephenyl)acetamide (2.9 G, 97 % yield) as a off-white solid.
Step 8 preparation of 5,7-dichloro-2-(4-((cyclopropylmethyl)sulfonyebenzy1)-6-(4,4-difluorop iperidin- 1 - y1)- 1H-benzo [el] imid azo le CI CI N
N\
CI NH2 Cl Ov µ0 %0 V
N- (2- amino -3 ,5 -dichloro-4 -(4,4-difluorop iperidin- 1 - yl)pheny1)-2 - (4-(cyclopropylmethylsu lfonyephenyl) acetamide (2.9 G, 5.45 mmol) was treated with acetic acid (20 mL), at 80 oC, for 2 hours. The acid was removed with high vacuum.
The residue was neutralized with NaHCO3 and absorbed onto silica gel. It was purified with 40% ethyl acetate in dichloromethane as eluent to get 2-(4-(cyclopropylmethylsulfonyl)benzy1)-5,7-

178 dichloro-6-(4,4-difluoropiperidin-1-y1)-1H-benzo[d]imidazole (2.3 G. 82 %
yield) as a brightly white solid.
Step 9 preparation of tert-butyl 5,7-dichloro-2-(4-((cyclopropylmethyl)sulfonyl)benz y1)-6-(4,4-diflu oropip eridin- 1 - y1)- 1H-b enzo [el] imidazo le- 1-c arbo xylate ci ci = N
\ r&-)...-CI
.... N Ni F01 H F-...0 Boc ,S
CI ,S=
F
To a solution of 2-(4- (cycloprop ylmethylsulfonyl)b enz y1)-5 ,7-dichloro-6- (4,4-difluorop iperidin-l-y1)-1H-benzo [d]imidazole (3.35 G, 6.51 mmol) in dichloromethane (50 mL) was added di-t-butyl-di-carbonate (1.25 G, 9.77 mmol), N, N-Diisopropylethylamine (1.7 mL, 9.77 mmol), and catalytic amount of DMAP. After addition, the reaction solution was stirred at ambient temperature for 6 hours. It was concentrated, and purified on a silica gel column, eluting with 50 % ethyl acetate in dichloromethane, to get tert-butyl 2-(4-(cyclopropylmethylsulfonyebenz y1)-5,7 -dichloro -6-(4 ,4-diflu oropiperidin-1 -y1)- 1 H-benzo [d]imidazole-1-carboxylate (3.62 G, 90 % yield) as a white solid.
Step 10 preparation of tert-butyl 5,7-dichloro-2-(1-(4-(cyclopropylmethylsulfonyl) phenyl)-3 -metho xy-3 -oxoprop y1)-6-(4 ,4-diflu oropip eridin- 1 -y1)- 1H-b enzo [el]
imidazole- 1 -c arbo xylate o CI . Br(C) CI N 001 N
\ r& .0 0 \ r& 1 Ni -)..- .0 N
F F ,S=
CI Boc ,S=
0' sO V CI Boc 0' sO V
F F
To a solution of tert-butyl 2-(4-(cyclopropylmethylsulfonyl)benzy1)-5,7-dichloro-6-(4,4-difluoropiperidin-1-y1)-1H-benzo [d]imidazole-l-carboxylate (8.2 G, 13.35 mmol) in THF
(150 mL) was added lithium bis(trimethylsilyl)amide (1 M in THF, 17.4 mL), at -78oC. After stirring at -78oc for half hour, methyl 2-bromoacetate (4.1 g, 26.70 mmol) was added, and the reaction was slowly warmed to ambient temperature, and stirred for 12 hours.
It was worked up with ethyl acetate and water. The organic layer was concentrated, and purified on a silica gel column, eluting with 40 % ethyl acetate in dichloromethane, to get tert-butyl 5,7-dichloro-2- (1 - (4-(c ycloprop ylmethylsulfo nyl)phe ny1)-3 -metho xy-3 -o xoprop y1)-6 -(4,4 -difluorop iperidin- 1 - y1)- 1H-benzo [d] imid azo le- 1 -carboxyl ate (6.3 g, 68.7 % yield) as a white solid.

179 Step 11 preparation of 3-(4-((cyclopropylmethyl)sulfonyl)pheny1)-3-(5,7-dichloro-6-(4,4-difluoropiperidin-l-y1)-1H-benzo [d] imid azol-2- y1)-1 -morpholinoprop an-1 -one CI
0 C ) N

N
*I 4 N\ 0 _,.... CI N

CI Boc Cl'AcV F0 CI 0'/ScV
F F
To a solution of tert-butyl 5,7-dichloro-2-(1-(4-(cyclopropylmethylsulfonyl)pheny1)-3-methoxy-3-oxopropy1)-6-(4,4-difluoropiperidin-l-y1)-1H-benzo [d]imidazole-l-carboxylate (350 mg, 0.51 mmol) in methanol (3 mL) was added morpholine (1 mL). The reaction solution was stirred at 100 oC for 14 hours. It was absorbed onto silica gel, and eluted with 60% ethyl acetate, to get 3-(4-(cyclopropylmethylsulfonyl)pheny1)-3-(5,7-dichloro-6-(4,4-difluoropiperidin- 1 - y1)- 1H-benzo [d]imidazol-2- y1)- 1 -morpholinoprop an-1 -one (310 mg, 94 % yield) as an off-white solid.
Step 12 Preparation of 4-(3-(4-((cyclopropylmethyl)sulfonyl)pheny1)-3-(5,7-dichloro-6-(4,4-difluoropiperidin- 1 - y1)- 1H-benzo [el] imid azol-2- yl)prop yl)morpho line C ) C ) N N

CI -Ipp..
.01 N 0 .01 N 101 s F H
F CI
CI Boc O'AcV
F F
To a solution of 3 - (4- (c ycloprop ylmethylsulfo nyl)pheny1)-3 -(5 ,7-dichloro-6 - (4,4-difluorop iperidin- 1 - y1)- 1H-benzo [d]imidazol-2- y1)- 1 -morpholinoprop an-1 -one (305 g, 0.48 mmol) in dry THF (10 mL) was added LAH (1 M in THF, 10 mL), at 0 C. After addition, the reaction solution was stirred at 0 C for 14 hours. It was purified on a reverse phase column to get 5 ,7 -dichloro -2- (1 - (4- (c yclopropylmethylsu lfo nyl)phe ny1)-3 -morpholinoprop y1)-6 -(4,4 -difluorop iperidin- 1 - y1)- 1H-benzo [d] imid azo le (100 mg, 33%
yield) as a white solid.
MS m/z (ESI): 627 [M+1].
1H NMR (400 mHz, CD30D): 7.92 (d, 10 Hz, 2 H), 7.69 (d, 10 Hz, 2 H), 7.55 (s, 1 H), 3.67 (m, 6 H), 3.58 (m, 1 H), 3.13 (m, 2 H), 2.62 (m, 1 H), 2.48-2.41 (m, 4 H), 2.38-2.31 (m, 2 H), 2.13 (m, 4 H), 1.61 (m, 1 H), 1.32 (m, 2 H), 0.95-0.91 (m, 2 H), 0.50 (m, 2 H), 0.11 (m, 2 H).

180 Example 171 Preparation of N-(3 -(4-((c yc loprop ylmethyl) su lfonyepheny1)-3 -(5 ,7-dichloro-6- (4,4 -difluorop iperidin- 1 - y1)-1H-b enzo [el] imidazol-2 - yl)prop yl)acetamide os,0 FN IP
CI N
H

N--r This compound can be prepared by the similar method as of example 170.
BIOLOGICAL ASSAY
The present invention will be further described with reference to the following test examples, but the examples should not be considered as limiting the scope of the invention.
Test Example 1. LanthaScreen TR-FRET Retinoid-Related Orphan Receptor gamma cRORy) Coactivator Assay Materials and Reagents 1. RORy LBD-GST tagged (Cat No. RORC-114H, Creative Biomart) 2. Fluorescein-D22 coactivator peptide (Cat No. PV4386, Invitrogen) 3. LanthaScreenTM Tb anti-GST antibody (Cat No. PV3550, Invitrogen) 4. TR-FRET coregulatory buffer D (Cat No, PV4420, Invitrogen) 5. DTT (Cat No. P2325, Fisher) 6. 384-well assay plate (Cat No. 6008280, Perkin Elmer) 7. Tecan Infinite M1000 plate reader (Tecan) Experimental procedure Prepare Complete TR-FRET Coregulator Buffer D by adding 1 M DTT to TR-FRET
Coregulator Buffer D to the final concentration of 5 mM DTT. Make compound dilution in Complete TR-FRET Coregulator Buffer D. Highest dose is 3 pM, 7-folder dilution for total 7 doses. Add 10 111_, to each well of a 384-well plate. For the negative and positive controls, add 10 pL of Complete TR-FRET Coregulator Buffer D.
Prepare RORy LBD using Complete TR-FRET Coregulator Buffer D. The final concentration of RORy LBD is 25 ng/reaction. Add 5 jut RORy LBD to all the wells of the 384-well assay plate except negative wells which adding 5 pL Complete TR-FRET
Coregulator Buffer D.

181 Prepare a solution containing 0.6 11M Fluorescein-D22 and 8 nM Tb anti-GST
antibody using Complete TR-FRET Coregulator Buffer D. Add 5 pL to all wells of the 384-well assay plate.
Briefly and gently mix the 384-well plate on a plate shaker and incubate at room .. temperature protected from light for 1 hour. The plate may be sealed with a cover to minimize evaporation.
Read the plate at wavelengths of 520 nm and 495 nm on Tecan Infinite M1000.

values were calculated using GraphPad Prism by plotting the logarithm of compounds concentration versus percent inhibition. The IC50 values for the example compounds were .. shown in Table I.
Test Example 2. IL-17 production assay using human PBMC
Materials and Reagents 1. Human PBMC cells (Cat No. 70025.1, Zenbio) 2. Lymphocyte medium (Cat No. LYMPH-1, Zenbio) 3. TexMACS (Cat No. 130-097-196, Miltenyi) 4. Cytostim-human (Cat No. 1130-092-173, Miltenyi) 5. Human IL-17 ELISA (Cat No. D1700, R&D systems) 6. Tecan Infinite M1000 plate reader (Tecan) Experimental procedure for IL-17 production assay Cryopreserved peripheral blood human mononuclear cells (PBMCs) were rapidly thawed in warmed Lymphocyte media, and centrifuged cell suspension at 1000 rpm for 10 minutes. The supernatant was removed, and the cell pellets were gently resuspended in TexMACS media.
Human PBMC cells in TexMACS media were plated at 1x105 each well in triplicate.
.. The test compounds at various concentrations or vehicle control (<0.5%
DMSO) were added into cell culture. The cells were stimulated by cytostim (10 ILIL/mL) for 3 days in a humidified, 5% CO2 incubator at 37 C.
After incubation, the cell culture supernatant was harvested, and then removed particulates by centrifugation. Human IL-17 in the supernatant was measured using human IL-17 ELISA kit according to the manufacturer's protocol. IC50 values were determined using GraphPad Prism by plotting the compounds concentration versus percent inhibition. The IC50 values for the example compounds were shown in Table I.

182 Table I
Example No. RORy Coactivator IL-17 production (ICso Assay (ICso 04) PM) 2 0.467 NIT
3 0.373 0.052 4 0.160 0.053 0.626 0.025 6 0.003 0.022 7 0.086 0.223 8 0.903 NIT
9 0.475 0.01 0.056 NIT
11 0.242 NIT
12 0.106 NIT
13 0.675 0.082 14 0.086 0.022 0.787 NIT
16 0.626 NIT
17 0.097 NIT
18 0.013 NIT
19 0.052 0.343 0.013 0.056 21 0.083 0.453 22 0.219 NIT
23 0.318 0.075 24 0.701 NIT
0.789 NIT
26 0.465 NIT
27 0.489 NIT
28 0.045 NIT
29 0.269 0.009 0.062 0.007

183 Example No. RORy Coactivator IL-17 production (ICso Assay (IC50 vilVI) 04) 31 0.01 0.011 32 0.052 0.007 33 0.031 0.015 34 0.016 0.049 35 0.061 0.008 36 0.348 N/T
37 0.433 N/T
38 0.147 0.873 39 0.007 0.038 40 0.083 N/T
41 0.683 N/T
42 0.113 N/T
43 0.656 N/T
44 0.026 N/T
45 0.535 N/T
46 0.048 0.018 47 0.196 N/T
48 0.445 N/T
49 0.255 N/T
50 0.284 N/T
51 0.646 N/T
52 0.135 N/T
53 0.575 N/T
54 0.367 N/T
55 0.194 N/T
56 0.879 N/T
57 0.187 N/T
58 0.266 N/T
59 0.433 N/T
60 0.409 N/T

184 Example No. RORy Coactivator IL-17 production (ICso Assay (IC50 04) PM) 61 0.509 N/T
62 0.154 N/T
63 0.592 N/T
64 0.465 N/T
65 0.015 N/T
66 0.002 0.01 67 0.002 0.002 68 0.03 0.004 69 0.007 0.056 70 0.014 0.006 71 0.004 N/T
72 0.006 0.003 73 0.029 0.001 74 0.187 N/T
75 0.006 N/T
76 0.387 N/T
77 0.021 0.017 78 0.028 0.069 79 0.048 N/T
80 0.031 0.013 81 0.035 0.003 82 0.046 N/T
83 0.065 N/T
84 0.019 0.013 85 0.188 N/D
86 0.075 0.023 87 0.024 N/T
88 0.162 N/T
89 0.004 N/T
90 0.004 N/T

185 Example No. RORy Coactivator IL-17 production (ICso Assay (IC50 04) PM) 91 0.140 N/T
92 0.067 N/T
93 0.075 N/T
94 0.023 N/T
95 0.065 N/T
96 0.123 N/T
97 0.001 N/T
98 0.007 N/T
99 0.025 0.0024 100 0.014 0.0013 104 0.082 N/T
102 0.062 N/T
103 0.158 N/T
104 0.337 N/T
106 0.003 N/T
107 0.055 N/T
108 0.032 N/T
109 1.04 N/T
110 0.698 N/T
111 0.06 N/T
112 0.076 N/T
113 0.18 N/T
114 0.564 N/T
115 0.171 N/T
116 0.235 N/T
117 0.149 N/T
118 0.306 N/T
119 0.034 0.124 120 0.321 N/T
121 0.966 N/T

186 Example No. RORy Coactivator IL-17 production (ICso Assay (IC50 M) PM) 122 0.049 N/T
123 0.030 0.058 124 0.205 0.032 the shorter retention time of 0.070 0.024 124-1 and 124-2 the longer retention time of 0.026 0.041 124-1 and 124-2 125 0.059 0.047 126 0.135 0.008 the shorter retention time of 0.014 0.045 126-1 and 126-2 the longer retention time of 0.036 0.031 126-1 and 126-2 127 0.22 0.013 128 0.006 0.091 129 0.014 0.242 133 0.024 0.027 134 0.006 0.003 135 0.039 0.014 136 0.005 0.014 137 0.013 0.004 138 0.018 0.009 the shorter retention time of 0.093 0.214 139 and 140 the longer retention time of 0.035 0.026 139 and 140 141 0.01 0.02 142 0.013 0.028 143 0.01 0.027 144 0.011 0.023 145 0.068 0.01

187 Example No. RORy Coactivator IL-17 production (ICso Assay (IC50 M) PM) the shorter retention time of 0.057 0.315 146 and 147 the longer retention time of 0.004 0.014 146 and 147 the shorter retention time of 1.41 0.555 148 and 149 the longer retention time of 0.083 0.022 148 and 149 the shorter retention time of 0.787 0.718 150 and 151 the longer retention time of 0.026 0.031 150 and 151 the shorter retention time of 0.21 0.86 152 and 153 the longer retention time of 0.013 0.010 152 and 153 154 0.049 0.077 the shorter retention time of 0.081 0.135 155 and 156 the longer retention time of 0.074 0.026 155 and 156 157 0.007 0.022 158 0.005 0.187 159 0.005 0.01 the shorter retention time of 0.003 0.006 160 and 161 the longer retention time of 0.003 0.004 160 and 161 the shorter retention time of 0.014 0.069 162 and 163 the longer retention time of 0.31 0.029

188 Example No. RORy Coactivator IL-17 production (ICso Assay (ICso 'LIM) 'LEM) 162 and 163 164 or 165 made from Int- 1.25 0.28 164 or 165 made from Int- 0.418 0.35 166 or 167 made from Int- 0.01 0.066 166 or 167 made from Int- 0.047 0.072 170 0.71 0.43 N/T: not tested The foregoing examples and description of the preferred embodiments should be taken as illustrating, rather than as limiting, the present invention as defined by the claims.
Numerous variations and combinations of the features set forth above may be utilized without departing from the present invention as set forth in the claims.

189

Claims (25)

PCT/US2019/030526What is claimed is:

1. A compound of formula (I):
R5a R5b a \ (R7)n (R4)s R3 4100 lo!
A r0 Rb R6 (1) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
¨ is a single bond or double bond; when ¨a is a double bond, then ¨ is a single bond, Ra is absent, and Rb is hydrogen; and when ¨ is a double bond, then ¨a is single bond, Ra is hydrogen, and Rb is absent;
ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and hetero aryl ;
Ri, R2, and R3 are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cyano, amino, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R4 at each occurrence is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -0R8, -C(0)0R8, -COR9, -NRioCOR9, -S(0)2R9, -NRioS(0)2R9, -CONRiiRi2, -NRiiR12, and -S(0)2NRi iR12, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted by one or more groups independently selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
Rsa and R5b are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, cyano, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, -0R8, -(CH2)xNRioCOR9, -NRioCOR9, -NRioCOCH2OR8, -(CH2)X(0)0R8, -(CH2)xCONRiiRi2, and -(CH2)xNRiiR12, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, -00NR11R12, _I\TR10C0R9, cycloalkyl, heterocyclyl, aryl, and hetero aryl ;
ssO R8 or R5a and R56 are together form II =
R6 is selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -NR11R12, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, .. nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R7 at each occurrence is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -0R8, -C(0)0R8, -COR9, -NRioCOR9, -S(0)2R9, -NRioS(0)2R9, -CONR11R12, -NR11R12, and -S(0)2NR11R12, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted by one or more group(s) selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R8 is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, and heterocyclyl, wherein said alkyl, aryl, and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen and alkoxy;
R9 is is selected from the group consisting of hydrogen, alkyl, hydroxyl, alkoxy, cycloalkyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
Rio is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
Ri 1 and R12 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, COR13, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
or R11 and Ri2 together with the nitrogen atom to which they are attached forma heterocyclyl group, wherein the heterocyclyl group comprises one or more additional heteroatoms independently selected from the group consisting of 0, N and S, and wherein the heterocyclyl group is optionally substituted by one or more groups independently selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
Ri3 is selected from the group consisting of hydrogen, alkyl, hydroxyl, alkoxy, cycloalkyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted by one or more groups independently selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
n is 0, 1, 2, 3, or 4;
s is 0, 1, 2, 3 or 4; and x is 0, 1, 2, 3 or 4.

2. The compound of claim 1, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having a structure of formula ( Ia ) or formula (lb):
R5a R5b R5a R5b (R7)n (R7)n (R4)s R3 N (R4)s R3 N
NH sO CI .41 sO

( la ) ( lb ) wherein:
Ri-R4, R5a, R5b, R6, R7, n and s are as defined in claim 1.

3. The compound of claim 1 or 2, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein ring A is selected from the group consisting of phenyl, C3_6 cycloalkyl, and 5 or 6 member heteroaryl, preferably piperidinyl, phenyl, thienyl, furyl, or pyridinyl.

4. The compound of any one of claims 1 to 3, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having a structure of formula ( II ):

R5a R5b Ra \ (R7) R3 n (R4)s, b:
N
it R Rb 0 6 ( I I ) wherein:
a b ¨ Ra, Rb, RiR4, R5a, R5b, R6, R7, n and s are as defined in claim 1.

5. The compound of any one of claims 1 to 4, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having a structure of formula ( IIa ):
Ra R5a R5b (R7) R3 N n a '1 bi N
R4 R2 R1Rb D
( I la ) wherein:
a b ¨ ¨ Ra, Rb, R1"-R4, R5a, R5b, R6, R7 and n are as defined in claim 1.

6. The compound of any one of claims 1 to 3, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having a structure of formula ( III ):
Ra \ R5a R5b R3 (R7) n (R4)s UN 41 bi II
Rb ( 11 1 ) wherein:
a b ¨ Ra, Rb, RiR4, R5a, R5b, R6, R7, n and s are as defined in claim 1.

7. The compound of any one of claims 1 to 3 or 6, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, having a structure of formula ( Ina ):

Ra R5a R5b R4R4a,cN R3 N (R7)n , b R

R2 R1 b ( Illa ) wherein:
R4a. and R4b are each independently selected from the group consisting of halogen, hydrogen, alkyl, and haloalkyl;
a b ¨ , Ra, Rb, R17-R3, R5a, R5b, R6, R7 and n are as defined in claim 1.

8. The compound of any one of claims 1 to 6, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R4 at each occurrence is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, -0R8, and -NR11R12;
Rg, Rii and Ri2 are as defined in claim 1.

9. The compound of any one of claims 1 to 8, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein Ri, R2, and R3 are each independently selected from the group consisting of hydrogen, halogen, and alkyl.

10. The compound of any one of claims 1 to 9, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R5a and R5b are each independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, -0R8, -(CH2)8NRioCOR9, -NRioCOR9, -NRioCOCH2OR8, _(CH2)8C(0)0R8, -(CH2)8CONRi iR12, and -(CH2)8NRi iRi2;
OR
N jsr 8 or R5a and R5b are together form II ; and tO Ri2 and x are as defined in claim 1.

11. The compound of any one of claims 1 to 10, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R6 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocyclyl, and -NRiiR12, wherein said alkyl is optionally substituted by one or more groups independently selected from the group consisting of alkoxy and cycloalkyl; and Rii and Ri2 are as defined in claim 1.

12. The compound of any one of claims 1 to 11, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R7 is selected from the group consisting of hydrogen, halogen, and alkyl.

13. The compound of any one of claims 1 to 3, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof,or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the compound is selected from the group consisting of:
¨\ 0 s ¨\ o ¨\ .o (:) ¨\s*o . -a o"s a o-s a 1, 11 II cl /N
N N
IN / /
N
HO H H
N CI N CI CF3 HO N ci OCF3 CI H

õS' 0' õS' 0 ' lik CI 0 CI 1, CI
Ilk CI
N * N N N
H
cl OCF3 N Cy-HO N HO N CI OCH, HO N CI OCH3 H H H

0 ¨
sõ
\S(D
(:) 1, CI
* CI = CI 1, N CI
p N N /

CI

HO N CI F HO N
H CI F
H H H

¨\ ,0 ¨\ ,0 ' ¨\ ,0 M .0 O''s' CI cy---s O's' 05' CI
II CI le CI I* N CI
* N
N
N / /
/ N CI 0'..--.0 CI'= HO hi CI (:)C) HO hl CI
N CI ON"---' H H

¨\ ,o ¨\ .0 ¨\ ,o - ¨\ o , -os o's_- 0-s 11 CI a li N 1, a 10 N CI
N N /
/

HO N CI (:)' HO N CI N CI (:)''0 H
H H H

¨\ ¨\ .0 ¨\ .0 ,C) C 0 ' ¨\ .0 S' ''S' Os --1, CI CI

N
N N
N /
/
HO H cl(1),0 HO N CI CN HO N CICN N CI
H H H

-\ .0 C) 01"S ' O,s -\ --¨\ ,0 ' ¨\ S ,AD
, -II CI ¨
S II CI ¨
o's cl CI
N
. II
/ / ,N N
HO N CI HO N CI N N N a OCHF2 H H H CI / H

¨\ -0 ¨\ 0 . 0 00S' 0'5 ¨\ 0 ¨\ , o"s S-C) * N CI
* N CI
* N CI 0' * N CI
/
ci OC2 N

N 0CF, H CI HO N CI
H H H

¨\ .0 ¨\ .0 ¨\ *
0 õ
0' O'S
* N CI
* CI
* CI
CI
00s-N / /1\I /NI
/
cl 0,C F3 N CF3 CF3 HO N CI HO N CI N CI
H H H H

¨\ õ0 ¨\ õ0 S' 0 . ' ' O's .5' 0' CI
* CI
* CI
* CI * N N N
N / /

/
HO-N N CI OCHF2 H2N N CI OCHF2 -NH hi a H H
H

¨\ ,o ¨\ .0 -.0 ¨\ , "C) 0-- , ' 0-'''s 01-s le a O's N II lik IF

\-NH hl a OCHF2 0 /
())=NH N a OCHF2 / V

/¨NH N CI

o H H
/
41 'I\1 42 43 44 \0 .
\ -0 \ , s- O'- 0 -- S
\s'(:) (:) 0' 0' CI
cl OCHF2 CI
CI * N CI
1, li ,NI /CIOY / N /N
II

H H

\ ,0 .s ' \--\ 0 \--\ 0 4. 01 CI 0 S', \--\ o CI o's' q_< a N N
N
HO
a OCHF2 / N H OC / N CI F3 HO NCI OCF3 ci OCF3 H H HO H

¨0 ¨0 ¨0 \--\ ' ,0 \--\ ,0 o \--\ .
O'S O'S' CDS' CD''.--1, CI
lik lik CI
= CI
CI
N N N N
/ /
NCI OCF, HO NCI OCF, HO N a OCF, N

H H H H

\ AD \ ,0 F\
' S". FJ F ) \ ,c) 0.1's 0*
7¨\ 0 F -* CI = CI F 0,S* 0*S
CI
N N q_( ci = N
/ N /
HO N a OCF3 HO N a OCH
ci OCF3 H H N
H c10CF3 HO N
H

F\ F\ F\
F
_0 .,S*
0*s*
0' 0" 0*S-* CI
= CI
* N CI
CI
*
N /1\I N
/
/ /
N ci OCF3 HO N a OCF, N CI CF3 H H H H

FS
Fc,0 0* O' s 6' , * > 53 ¨\ õ0 [1 ¨ \
, , ' -* CI * CI O's CI
/1\I N * N = N
N CI CF3 N a OCF3 HO N ci OCF3 HO N a OCF, H H H H

[>--\ ,0 0*S- >---\ -0 c)*"-= N CI
/ * /1\I CI
= CI
* CI
N N

O" I>¨Th -0 F\
0s )7F
11 CI 0*S-0 0s - *
=

F
N
* CI
/ N
N --.1--- 411 HN
ci OCH F2 / N /
N F
HO
H HO CI F HO N CI ---N CI
H H

F\
F )7F F, F
s)\¨F a 0 F
Cl 0 F 0 CI cF, y¨F

g00 g00 0 ,...õ, HN
HN HN A..õ.,g,0 F OH = a F OH
F OH

F, ) f F, F, F, ,F y¨F )¨F ¨F
y-F CI 0 0 00 o a o a o 0 ,6\,,g g00 g-,0 '''--- 0 HN ....-- HN

--N a F OH --N = CI
F F
OH

F\
)¨F FS Fs F Fµ ,F
CI 0 X¨F y¨F y¨F

g00 0 0 -,... HN g,0 g00 . 0,0 ',---- 0 HN ,.....- HN .1,..-g 0 HN
CI a F OH
CI CI OH

Fµ F)f-FF Fj i-F Y-F cl 0 7-F
0 cl 0 a 0 0 a 0 (:,,0 0 ,n,,,,,,,,,C8,0 A,..,,g,0 HN HN
'---- 0 HN 0 0 HN
--14 cl --N a -14 CI CI cl OH

CI CI CI CI a NC

,,,,,g,0 A0g,,c) CI NC Aj,o HN 0 HN

--NI ci --'1\1 CI --N CI
OH OH

F
F\
CI NC )- )-F

-F ci 0 0 .A.,._.,,g,0 0 HN . HN
6j, o 0 HN 0 HN
--N ci OH CI F OH F OH

FS FS
FS y-F y-F FS
y-F CI 0 CI 0 y¨F
a o o o a o o g,o 11,0 ,s- 0 g,0 HN
.- HN ----T- 0 HN, --N CI N CI
N CI
CI CI OH

FS FJ
y¨F T-F -- ,0 FS

g,0 11.0 -I F 0 0 HN T"S
-, -' 0 HN * N CI
g,0 CI
HN
N a N CF, N F
OH OH

F\ ,F
F ol-F

YF F F
F F

g,0 --',-- 0 HN --',-- 0 HN --'--- 0 HN

¨\ -0 , -F O'S

g,0 0 0 g,0 II 0 F 0 HN g,0 ---,-- 0 HN N '......- 0 HN
i N
\ N
OH H

F\ , 1,F Fµ ,F
/ /-F -F

0 g,0 0 g,0 _9g,0 g,0 --,-- 0 HN *--"--- 0 HN - 0 HN --',-- N 0 HN
-N ---N - --N
OH

FS
y-F F F
F 0 )7F )7F

A, Cgõ0 A, Cgõ0 HN N' 0 HN N' 0 HN
Itir H H
--N -N CI
OH

1\131-1 Çl Viz ----1---' H
N
N 1. N/ \N 0 N
d7) 10 * 10 1.õ..,......, . 0 A \_s, A A
53013 ',, A

O ,...r... Zvi. d, 0 T,d O 091.
OH

'FIN
H HO
N H 'FIN
H .
\N 0 N
N 0 \N
d_/01 N

0 *
d ,S , d 0 0,, 0 H HO
H 13 am N IO glim N o AI N
µ1111111 / /
N N WI
d7C1J1 WV N N N
o = A-T.,...) 10 10 d d jjjj Sz013 npj3 J

gu 10 0--.."- LC I- io O'N
g Ci-Mb f\--\
011 * HN- --S H N

OH
HO
,--0 0 Se 0 0' )--b...1 91, t>-...\ i'c 0 H n 0j---01 . HN 0 N
0 L>---\
f>-µS HN
0 -N la -I\I 10 Oi 4 HN
-N n 0'6 HO OH
HO
0 I.I. NI. A
ZEI, 10 0-1-- 'FIN 6Z1 d-( ,S 4HN
011 11 = Najd 0 HN .
'N Nilajd &=-6) 0 -N 0 71,0 8 0 10 HN
O N
HN

EZ za Z-9Z Hau HO, HO
0 H H 1, H EN4 0 õ - N 0 io zHN N
\ 0 . Na, w i, = Na,, ic=*NaA
/* N 0õ1õ.A
o A VW''o o , ....."
ro10 13 CrO
9Z l ga OH T-OZT OH
HO
H 0 13 1\k 0 .. 1µ1õ.(0) * " 0* 7 46 N(s) NH ,, NH Rgml Qj2S

c0 -- --9ZSO0/6IOZSIILL3c1 <c_Et02s EtO2S ,p N N ,P
Y
* 01 roLF
p N
* r-D-F 0 1110 /1\I
N CI \' N CI N

OH
H2N 146 H2N 147 Et0 <c_ g0 , <k_ _ ' p Y
Y s s Y
6 ,mW , o eII o 61, o N
/
N CI N CI

OH

<Lz g_0 Y <0 Y
o 4( 1, 0 I.
N *
N
N
/
N H CI N CI N
H CI
H
HO HO

p F,T.,F
c_ s <::: p F,T, F
F,T, F
FyF
6' o 6 Of o 6 q4,1 o s /
N
H
N CI N CI
FIN N CI N oH
ci O OH OH
, Et0 H2N 152 H2N 153 CI
0 \ ,0 <S_ ,p F,T,F .<_ip FF .<_ FF
sSc.,_. e FF-CNI * N 0 ,,, 0 0 lk dW 6.
a N
O / /
N NH2 CI N CI ' N CI
H
H H

os p `s¨ osp 0 ,0 F
t..
µss______4 F
* '..
FF-C
N * N
µ lel F0CI
N
\ F,LOCI N
CI N N
H H N

CI H

OH OH

a CI CI 0 \ ,0 0 ,0 0 0 F.X2 FN * 0 Sc4 µssc____A FFC
N afr N
µS \----4 F N 41 0 F- N
I
01 N a N 0 H i H i H
r 0,--CI <c_g, 0 <C¨e0 FyF
o W
0µ,C) dm, F o F.cN N ,s...õ4 W
N N
CI N
H N CI ' N CI

N ciN

163 o ¨) 164 0 165 <c_p FF <c_ P s FF
s 6 0 0' F
W W N F,1,OCI N
IN
\
H CI N
H
H
HN

0 ,0 V¨v F

04,7,6, CI
0, 0 sa, F
F)CN . N
N CI N CI N
H H
169 170 C ) 0 N TO
171 0 and .

14. A compound of formula ( IA ):
Ra \ R5a R5b R3 N A (R7)n Br 41 b 0, N
, Y
R2 R1 Rb 6 R6 ( IA ) , or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
¨ is a single bond or double bond; when ¨a is a double bond, then ¨b is a single bond, Ra is absent, and Rb is hydrogen; and when ¨b is a double bond, then ¨a is single bond, Ra is hydrogen, and Rb is absent;
Ri, R2, and R3 are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cyano, amino, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R5a and R5b are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, cyano, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, -0R8, -(CH2)81\TRi oCOR9, -NRioCOR9, -NRioCOCH2OR8, -(CH2)8C(0)0R8, -(CH2)8CONRiiRi2, and -(CH2)81\TRiiR12, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, -00NR11R12, _I\TR10C0R9, cycloalkyl, heterocyclyl, aryl, and hetero aryl ;
,s0 R8 or R5a and R56 are together form II
R6 is selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -NR11R12, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R7 at each occurrence is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -0R8, -C(0)0R8, -COR9, -NRioCOR9, -S(0)2R9, -NRioS(0)2R9, -CONR11R12, -NR11R12, and -S(0)2NR11R12, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted by one or more group(s) selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R8 is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, and heterocyclyl, wherein said alkyl, aryl, and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen and alkoxy;
R9 is is selected from the group consisting of hydrogen, alkyl, hydroxyl, alkoxy, cycloalkyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
Rio is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
Ri 1 and R12 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, COR13, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

or R11 and Ri2 together with the nitrogen atom to which they are attached forma heterocyclyl group, wherein the heterocyclyl group comprises one or more additional heteroatoms independently selected from the group consisting of 0, N and S, and wherein the heterocyclyl group is optionally substituted by one or more groups independently selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroarybRi3 is selected from the group consisting of hydrogen, alkyl, hydroxyl, alkoxy, cycloalkyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted by one or more groups independently selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
n is 0, 1, 2, 3, or 4; andx is 0, 1, 2, 3 or 4.

15. The compound of claim 14, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the compound is selected from the group consisting of:
¨\ ,o - CI
O's 0 li CI
HN 11 Br N-, F Br41 NH 40 p N CI /S

H F
¨\ -0 >--\ -O''s-OS
lik N Br _____________________________________ /NI Br / 11" Br = C 0 HN

N N I
H N CI and H .

16. A compound of formula ( IC ) or formula ( ID ), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, Ra (R4)s co R3 aµ
R R5a R5b (R7)n I
NH 0 (R4)S0 R5a R5b D el 0 I
rk2 NH SC3' Rb s--O
I li R
Ri ri\
R1 Rb 0 6 R2 0 R6 ( IC ) ( ID ) , , wherein:
Ra and Rb is hydrogen;

ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and hetero aryl ;
Ri, R2, and R3 are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cyano, amino, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R4 at each occurrence is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -0R8, -C(0)0R8, -COR9, -NRioCOR9, -S(0)2R9, -NRioS(0)2R9, -CONRiiRi2, -NRiiR12, and -S(0)2NRi iR12, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted by one or more groups independently selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R5a and R5b are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, cyano, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, -0R8, -(CH2)xNRioCOR9, -NRiOCOR9, -NRioCOCH2OR8, -(CH2)C(0)0R8, -(CH2)xCONRi iR12, and -(CH2)xNRi iR12, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, -CONRiiRi2, _NRioCOR9, cycloalkyl, heterocyclyl, aryl, and hetero aryl ;
ss0R8 or Rsa and R5b are together form II =
R6 is selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -NRiiR12, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R7 at each occurrence is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -0R8, -C(0)0R8, -COR9, -NRioCOR9, -S(0)2R9, -NRioS(0)2R9, -CONRiiRi2, -NRiiR12, and -S(0)2NRi iR12, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted by one or more group(s) selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R8 is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, and heterocyclyl, wherein said alkyl, aryl, and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen and alkoxy;
R9 is is selected from the group consisting of hydrogen, alkyl, hydroxyl, alkoxy, cycloalkyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
Rio is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, and heterocyclyl;
Ri 1 and Ri2 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, COR13, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
or Ri 1 and Ri2 together with the nitrogen atom to which they are attached forma heterocyclyl group, wherein the heterocyclyl group comprises one or more additional heteroatoms independently selected from the group consisting of 0, N and S, and wherein the heterocyclyl group is optionally substituted by one or more groups independently selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
Ri3 is selected from the group consisting of hydrogen, alkyl, hydroxyl, alkoxy, cycloalkyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted by one or more groups independently selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
n is 0, 1, 2, 3, or 4;
s is 0, 1, 2, 3 or 4; and x is 0, 1, 2, 3 or 4.

17. The compound of claim 16, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein the compound is selected from the group consisting of:
OH
0 0, ?
CI NH2 0.11 \----N 40 0 ,s,7 CI N

F---..) CI H F-701 Ilc 11 F OH F
H

a (i (:)ovL CI
0 NH20 4, _...0 N
F CI H F--N) 01 F F
F
0 CI r/¨F
Et0 F EtO2S 0H2N * N
I C r.LF
H N CI
N * N H
Et0 EtO2S 0 Y
0 ---...<

0 Et0 /g,o N
N CI
0 H2N Et0 H
.V.0 CI

Fy F
0 FyF 0 o Et0 0 H2N
H
N
N CI
H
0 Et0 .71'0 H2N CI
0 and o .

18. A process for preparing the compound of formula (I), comprising a step of coupling a compound of formula ( IA ) with a compound of formula ( IB ) under an alkaline condition in the presence of a catalyst:
Ra R5a R5b (R4)5 R Rsa R5b \
R3 N)c OR O G (R4)s 7)n a N
R3 N R:)n .--1 .---- A 'i'l A, Br 44/ bIN , I
C) ss, ( l B) CO 411 bI
N
ii '..".
Rb 0 R6 Rb 0 R6 ( IA ) ( I ) , wherein:

G is a leaving group, preferably boronic acid or borate; and a b ring A, ¨ , ¨ , Ra, Rb, RiR4,R5a, R5b, R6, R7, n and s are as defined in claim 1.

19. A process for preparing the compound of formula (I), comprising a step of cyclizing a compound of formula ( IC ) or formula (ID):
Ra R Ra R5a R5b ( R5a R5b Ra R R5b (R4)aCO R3 H (R4)s N 0 R7)n R3N5a P7)n WV 1 3 \N b^ 01 0 (ReOs I or CORb Rb rc0 R2 NH F-c0 rR6 R1 Rb2 0R6 ( IC ) ( ID ) ( I ) wherein:
a b ring A, ¨ ¨ Ra, Rb, RiR4, R5a, R56, R6, R7, n and s are as defined in claim 1.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

21. A method for inhibition of a retinoid-related orphan receptor gamma (RORy), comprising contacting a biological sample comprising RORy with a compound according to any one of claims 1 to 13, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or the pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition of claim 20.

22. A method for treating a retinoid-related orphan receptor gamma (RORy) mediated disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound according to any one of claims 1 to 13, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or the pharmaceutically composition of claim 20.

23. The method of claim 22, wherein the RORy mediated disease or disorder is selected from the group consisting of inflammation, autoimmune diseases and cancers, wherein the inflammation and autoimmune diseases comprise arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, osteoarthritis, regional entrritis, ulcerative colitis, ankylosing spondylitis, autoimmune diabetes, type I diabetes, autoimmune ocular disease, autoimmune thyroid disease, autoimmune polyedocrine syndrome type I, autoimmune polyendocrine syndrome type II, multiple sclerosis, inflammatory bowel disease, inflammatory bowel syndrome, juvenile idiopathic arthritis, Sjogren's syndrome, Crohn's disease, asthma, Kawasaki Disease, Hashimoto's thyroiditis, infectious diseases, ankylosing spondylitis, chronic obstructive pulmonary disease (COPD), pulmonary disease, glomerulonephritis, myocarditis, thyroiditis, dry eye, Uveitis, Behcet's disease, asthma, atopic dermatitis, contact dermatitis, allograft rejection, polymyocitis, grad versus host disease, acne, ulcerative colitis, s ystemic lupus erythematosus, scleroderma, bronchitis, dermatomyositis, and allergic rhinitis.

24. Use of a compound according to any one of claims 1 to 13, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition of claim 20, in the manufacture of a medicament for the treatment of a RORy mediated disease or disorder.

25. The use of claim 24, wherein the RORy mediated disease or disorder is selected from the group consisting of inflammation, autoimmune diseases and cancers, wherein the inflammation and autoimmune diseases comprise arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, osteoarthritis, regional entrritis, ulcerative colitis, ankylosing spondylitis, autoimmune diabetes, type I diabetes, autoimmune ocular disease, autoimmune thyroid disease, autoimmune polyedocrine syndrome type I, autoimmune polyendocrine syndrome type II, multiple sclerosis, inflammatory bowel disease, inflammatory bowel syndrome, juvenile idiopathic arthritis, Sjogren's syndrome, Crohn's disease, asthma, Kawasaki Disease, Hashimoto's thyroiditis, infectious diseases, ankylosing spondylitis, chronic obstructive pulmonary disease (COPD), pulmonary disease, glomerulonephritis, myocarditis, thyroiditis, dry eye, Uveitis, Behcet's disease, asthma, atopic dermatitis, contact dermatitis, allograft rejection, polymyocitis, grad versus host disease, acne, ulcerative colitis, s ystemic lupus erythematosus, scleroderma, bronchitis, dermatomyositis, and allergic rhinitis.